@article {pmid42506306,
year = {2026},
author = {Vamanu, A and Mastaleru, A and Schreiner, TG and Popescu, G and Roceanu, AM and Cucu, AI and Patrascu, A and Vulpoi, GA and Bilcu, RV and Cozma, RS and Olariu, R and Bistriceanu, CE and Covali, R and Cuciureanu, DI and Ciubotaru, A},
title = {Pharmacological and Clinical Heterogeneity of Anti-Amyloid Monoclonal Antibodies in Early Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Trials.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/medsci14030337},
pmid = {42506306},
issn = {2076-3271},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Biomarkers ; },
abstract = {Background: Anti-amyloid monoclonal antibodies represent the first disease-modifying therapeutic strategy targeting amyloid-β pathology in early Alzheimer's disease (AD). Although several agents have demonstrated the ability to reduce cerebral amyloid burden, their clinical efficacy and safety remain subjects of substantial scientific and regulatory debate. This study aimed to synthesize randomized evidence evaluating the benefit-risk profile of anti-amyloid monoclonal antibodies in biomarker-confirmed early AD. Methods: A systematic review and classical pairwise meta-analysis of randomized controlled trials (RCTs) was conducted following the PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for phase III placebo-controlled trials evaluating lecanemab, donanemab, aducanumab, and gantenerumab in patients with mild cognitive impairment due to AD or mild AD dementia with biomarker confirmation of amyloid pathology. The primary outcome was change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at the longest available follow-up. Safety outcomes included amyloid-related imaging abnormalities with edema or effusion (ARIA-E), amyloid-related imaging abnormalities with hemorrhage (ARIA-H), serious adverse events, and treatment discontinuation. Random-effects meta-analyses were performed. Results: Six randomized comparisons derived from four phase III trials involving 7695 participants met the eligibility criteria. Anti-amyloid monoclonal antibodies were associated with a statistically significant slowing of clinical progression compared with placebo (pooled mean difference in CDR-SB: -0.42 points; 95% CI -0.59 to -0.25; I[2] = 78%). The observed effect was primarily driven by trials of lecanemab and donanemab, whereas aducanumab demonstrated discordant results across trials and gantenerumab showed no clinically meaningful benefit. Despite statistical significance, the magnitude of the pooled effect approached the lower boundary of the minimal clinically important difference reported for CDR-SB in early AD. Treatment was associated with a markedly increased risk of ARIA-E (pooled risk ratio 10.1; 95% CI 7.8-13.0), with moderate heterogeneity across studies. Most ARIA-E events were asymptomatic and detected through protocol-mandated MRI monitoring. Conclusions: In biomarker-confirmed early Alzheimer's disease, anti-amyloid monoclonal antibodies produce a statistically significant but modest slowing of clinical decline accompanied by a substantially increased risk of ARIA. The benefit-risk profile appears heterogeneous across individual antibodies and may reflect pharmacological differences in amyloid targeting and clearance mechanisms. These findings support cautious, individualized use of anti-amyloid therapies and highlight the need for longer-term studies to determine whether short-term slowing of decline translates into clinically meaningful disease modification.},
}

Humans
*Alzheimer Disease/drug therapy
Randomized Controlled Trials as Topic
*Antibodies, Monoclonal/therapeutic use/pharmacology
*Amyloid beta-Peptides/antagonists & inhibitors/immunology
Antibodies, Monoclonal, Humanized/therapeutic use
Biomarkers

@article {pmid42506779,
year = {2026},
author = {Talwar, A and Sherer, J and Abughosh, S and Chatterjee, S and Aparasu, RR},
title = {Cumulative Anticholinergic Burden and Risk of Delirium Among Older Adults with Alzheimer's Disease.},
journal = {Pharmacy (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/pharmacy14040089},
pmid = {42506779},
issn = {2226-4787},
abstract = {Delirium is a transient neuropsychiatric condition that is a severe and prevalent condition affecting 2.6 million older adults each year. Alzheimer's disease (AD) and anticholinergic medication use are risk factors for delirium. This study evaluated the association between cumulative anticholinergic burden (CAB) and risk of delirium among older adults with AD initiating cholinesterase inhibitors (ChEIs). This retrospective cohort study used 2013-2017 Medicare claims data, and included adults 65 years and older with AD who initiated any of the ChEIs (donepezil, rivastigmine, and galantamine) after a 12-month washout period. CAB, as the primary exposure, was measured on the index date and calculated as the monthly total standardized daily dose of anticholinergic medications. A multivariable Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) generated using generalized boosted models was used to evaluate the risk of delirium associated with the CAB. This study identified 143,320 older adults with AD who initiated ChEIs. Most patients were in the low/no burden (62.73%) group, followed by high burden (21.12%) and moderate burden (16.14%). Overall, delirium diagnosis was observed in 19.11% of the cohort. The Cox regression model with IPTW found that moderate (aHR, 1.56; 95% CI, 1.52-1.61; p < 0.0001) and high CAB (aHR, 1.45; 95% CI, 1.42-1.49; p < 0.0001) were associated with an increased risk of delirium compared to low/no burden. Among older adults with AD initiating ChEIs, moderate and high CAB were associated with an increased risk of delirium compared with low/no CAB. These findings highlight the need to carefully reduce the CAB, especially dose and duration, along with utilizing anticholinergic alternatives in older adults with AD.},
}

@article {pmid42506943,
year = {2026},
author = {Periyasamy, TS and Sekar, N and Lakshmanan, H},
title = {Integration of multi-omics and artificial intelligence for therapeutic insights in Alzheimer's disease: A comprehensive review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471812},
doi = {10.1177/13872877261471812},
pmid = {42506943},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a progressively worsening type of brain disorder that damages the nerve cells. It is marked by the buildup of amyloid-β plaques outside the cells, tau neurofibrillary tangles inside the cells, and overall molecular-level dysfunction. The therapies currently available mainly cater to alleviating the symptoms, whereas the newly approved disease-modifying antibodies, such as lecanemab and donanemab, bring out only limited clinical improvements. Being complicated and involving many factors, AD requires sophisticated computer-based methods to combine different biological data and find suitable therapy targets. In this review, we discuss how artificial intelligence (AI)-powered multi-omics data integration can be a catalyst in discovering drug targets, identifying biomarkers, and stratifying patients for AD. By utilizing machine learning techniques like random forests, graph neural networks, and deep learning, AI-led multi-omics methods have helped uncover new therapeutic targets. Models that were built using federated learning across various institutions outperformed single-center models with a higher area under the curve score (0.84, 0.94 versus 0.76, 0.85). AI-guided patient stratification lessened the clinical trial's sample size needs by 40, 55% while still retaining 80, 90% statistical power. Multi-omics analyses further pointed out that it is the downstream molecular pathways, and not amyloid pathology alone, that are significantly involved in disease progression, thereby questioning the effectiveness of single-target anti-amyloid therapies and endorsing combination treatment strategies. AI and multi-omics data combination can be a game-changer in facilitating new target discovery, making clinical trial design more efficient, and ushering in precision medicine in AD.},
}

@article {pmid42507054,
year = {2026},
author = {Otomi, Y and Shinya, T and Otsuka, H and Kasai, H and Matsushita, T and Takaoka, Y and Hiroshima, Y and Matsubara, T and Fujita, K and Tomioka, Y and Nakataki, M and Numata, S and Izumi, Y and Harada, M},
title = {Serial amyloid PET demonstrates marked reduction in amyloid burden following donanemab treatment: a real-world cohort study.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42507054},
issn = {1867-108X},
support = {JP24K15767//Japan Society for the Promotion of Science/ ; },
abstract = {PURPOSE: To evaluate changes in amyloid burden on serial amyloid PET before and after donanemab treatment in a real-world clinical cohort.

METHODS: This retrospective study included 20 consecutive patients who underwent serial amyloid PET before and after donanemab treatment. Quantitative analysis was performed using Centiloid values and tracer-specific standardized uptake value ratios (SUVr). Visual assessment was also performed to determine amyloid-positive or amyloid-negative status before and after treatment.

RESULTS: Centiloid values significantly decreased from 52.3 ± 23.4 at baseline to - 5.6 ± 16.5 at follow-up, with a mean change of - 58.0 (p < 0.001). All patients showed a reduction in Centiloid values. In the flutemetamol group (n = 12), pons-referenced SUVr significantly decreased, while in the florbetapir group (n = 8), cerebellar-referenced SUVr also showed significant reductions (both p < 0.001). On visual assessment, 17 of 20 patients (85%) converted from amyloid-positive to amyloid-negative status after treatment.

CONCLUSION: Serial amyloid PET demonstrated a substantial reduction in amyloid burden following donanemab treatment in this real-world cohort. Quantitative amyloid PET, particularly using Centiloid scaling, may be a useful tool for monitoring treatment response in clinical practice.},
}

@article {pmid42507235,
year = {2026},
author = {Stites, SD and Lee, K and Kuz, C and Mandell, D and Bogner, HR and Brown, R},
title = {Worry and Anxiety in the Era of Early Diagnosis and Disease Modifying Treatment for Alzheimer's Disease.},
journal = {Current psychiatry reports},
volume = {28},
number = {1},
pages = {},
pmid = {42507235},
issn = {1535-1645},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology/therapy ; Early Diagnosis ; *Anxiety/psychology/diagnosis ; },
abstract = {PURPOSE OF REVIEW: Psychologists and psychiatrists are well-positioned to be at the forefront of addressing the challenges posed by anxiety in early diagnosis and treatment of Alzheimer's disease (AD) dementia that are unfolding in primary care settings. The present article provides a summary of emerging areas in Alzheimer's disease testing and research to guide clinical decisions and research pursuits.

RECENT FINDINGS: The present article provides an overview of how anxiety is understood in early diagnosis of dementia due to AD, its influence in AD-related mechanisms, and the implications of these findings on current research practices. We conducted focused literature reviews between January and June 2026 and synthesized the information to provide a narrative review. Overall, the clinical roles of anxiety in AD dementia are expanding- from being viewed primarily as reactions to cognitive decline to serving as informative features of the diagnostic process and clinical course of the disease.},
}

Humans
*Alzheimer Disease/diagnosis/psychology/therapy
Early Diagnosis
*Anxiety/psychology/diagnosis

@article {pmid42507320,
year = {2026},
author = {Wang, C and Han, X and Lin, Y and Pan, Y and Miao, Q and Wang, Y and Wang, SQ and Zhang, Z and Wang, L and Tang, ZR and Peng, Y and Yung, KK and Ma, N and Lu, D and Zhang, S and Shi, L},
title = {Betulinaldehyde Ameliorates Aβ-Induced Neurotoxicity and Cognitive Deficits by Modulating the eEF2K/eEF2 Pathway.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {7},
pages = {e71050},
pmid = {42507320},
issn = {1755-5949},
support = {2022YFA1104900//National Key Research and Development Program of China/ ; 2022ZD0214400//The Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 82371175//National Natural Science Foundation of China/ ; U24A20804//National Natural Science Foundation of China/ ; 2023A1515030012//Guangdong Basic and Applied Basic Research Foundation/ ; 2022B1515130007//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515040015//Guangdong Basic and Applied Basic Research Foundation/ ; 202102070001//The Science and Technology Projects in Guangzhou/ ; 2023A0505050121//International Science and Technology Projects of Guangdong Province/ ; 20261073//The Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Elongation Factor 2 Kinase/metabolism ; Mice ; *Peptide Fragments/toxicity ; *Triterpenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Neurons/drug effects ; *Cognition Disorders/drug therapy/chemically induced ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, remains without effective therapies. Dysregulated eukaryotic elongation factor 2 kinase/eukaryotic elongation factor 2 (eEF2K/eEF2) pathway leads to aberrant protein synthesis and impaired neuronal function in AD, positioning this axis as a promising therapeutic target. However, effective pharmacological modulators of eEF2K/eEF2 remain limited. Betulinaldehyde (Betu), an active ingredient derived from traditional Chinese medicine, remains to be thoroughly evaluated as a potential neuroprotective agent.

PURPOSE: This study aims to investigate the therapeutic effects of Betu on AD and determine whether its activities are mediated through the eEF2K/eEF2 pathway.

METHODS: Neuronal cell models were used to assess the effects of Betu on β-amyloid 42 (Aβ42)-induced neuronal death, dendritic spine damage, protein synthesis inhibition, and eEF2 hyperphosphorylation. The eEF2K agonist nelfinavir (NFV) and the protein synthesis inhibitors cycloheximide (CHX) and anisomycin (AS) were used to investigate the involvement of the eEF2K/eEF2 pathway and its regulated protein synthesis in the action of Betu. The cellular thermal shift assay (CETSA) was used to detect potential interactions between Betu and eEF2K. Additionally, the effects of Betu on reactive oxygen species (ROS) levels and the associated pathways were evaluated. An Aβ42-induced mouse model of AD was used to evaluate the in vivo effects of Betu on cognitive decline, hippocampal neuropathological damage, and eEF2 hyperphosphorylation.

RESULTS: Betu significantly ameliorated the Aβ42-induced neuronal death and dendritic spine damage, restored protein synthesis, and reversed eEF2 hyperphosphorylation. The neuroprotective effects of Betu were effectively inhibited by the CHX, AS, or NFV treatment, and CETSA supported a potential interaction between Betu and eEF2K. Furthermore, Betu reversed Aβ42-induced ROS accumulation and upregulated nuclear factor-like 2 and heme oxygenase-1, potential downstream effectors of the eEF2K pathway. In an Aβ42-induced AD mouse model, Betu treatment markedly ameliorated cognitive decline, concomitant with attenuated neuropathological damage and restored eEF2 phosphorylation in the hippocampus.

CONCLUSION: These findings demonstrate that Betu protects against Aβ42-induced neurotoxicity by modulating the eEF2K/eEF2 pathway, highlighting its potential as a lead compound for AD.},
}

Animals
*Amyloid beta-Peptides/toxicity
*Elongation Factor 2 Kinase/metabolism
Mice
*Peptide Fragments/toxicity
*Triterpenes/pharmacology/therapeutic use
Signal Transduction/drug effects
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
Neurons/drug effects
*Cognition Disorders/drug therapy/chemically induced
Mice, Inbred C57BL

@article {pmid42507332,
year = {2026},
author = {Liao, C and Sun, D and Wang, X},
title = {Disease mechanisms and translational barriers guide nanocarrier design for nose to brain delivery in Alzheimer's disease.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {42507332},
issn = {2731-9229},
support = {82572661//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying treatment options, partly because many therapeutic agents show insufficient brain exposure and dose-limiting systemic adverse effects after conventional administration. Nose-to-brain (N2B) delivery has emerged as a non-invasive strategy to transport therapeutics to the central nervous system through the olfactory and trigeminal pathways, thereby partially bypassing the blood-brain barrier. Recent advances in nanomedicine and biomaterial engineering have further improved this approach by enhancing drug stability, nasal residence, mucosal transport, and brain-targeting efficiency. This review examines nanocarrier-enabled N2B delivery strategies for AD from a mechanism-guided perspective, highlighting how AD-related pathological processes shape the selection of therapeutic cargos and formulation designs. We discuss recent progress in the intranasal delivery of repurposed small molecules, natural products, insulin-related agents, peptides and proteins, extracellular vesicles, antibodies, and nucleic acid-based therapeutics. We further summarize major nanocarrier and formulation platforms, including lipid-based systems, polymeric nanoparticles, micelles, extracellular vesicles, in situ gels, and device-assisted delivery technologies. Particular attention is given to the design parameters that influence N2B performance, including particle size distribution/PDI, surface charge, mucus interaction, cargo protection, targeting modification, biodistribution, and deposition reproducibility. Finally, we critically evaluate the translational challenges that continue to limit clinical application, including species differences in nasal anatomy, dose-volume restrictions, device-dependent variability, limited human pharmacokinetic evidence, manufacturing complexity, long-term safety, and regulatory requirements. By integrating disease mechanisms, nanocarrier design, and translational considerations, this review provides a structured perspective for developing more rational and clinically feasible N2B nanodelivery systems for AD.},
}

@article {pmid42508295,
year = {2026},
author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y},
title = {Discovery of a CI-994 derivative as a dual modulator of class I histone deacetylases and Wnt/β-catenin signaling for Alzheimer's disease therapy.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e00974},
doi = {10.1016/j.neurot.2026.e00974},
pmid = {42508295},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC50 values of 0.51 μM, 0.68 μM and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, suppresses tau phosphorylation, and reduces Aβ levels in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.},
}

@article {pmid42508316,
year = {2026},
author = {Wang, D and Huang, W and Wang, X and Zhang, L and Tao, X and Qin, F and Guo, S and Han, G and Zhang, Z},
title = {Fluorescence lifetime imaging of G-quadruplex RNA dynamics in Alzheimer's disease using a novel nucleic acid-sensitive probe.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130351},
doi = {10.1016/j.talanta.2026.130351},
pmid = {42508316},
issn = {1873-3573},
abstract = {Real-time monitoring of G-quadruplex (G4) RNA dynamics is vital for understanding their biological roles in the progression and treatment of Alzheimer's disease. However, this remains challenging due to two key difficulties. First, current fluorescent probes lack sufficient selectivity for G4 RNA over G4 DNA and other non-G4 secondary structures in live-cell competitive environments. Second, fluorescence intensity-based imaging cannot detect subtle changes in G4 RNA because of variations in fluorophore uptake and photobleaching. Herein, we report a novel thiazole orange derivative (TOGR) for fluorescence lifetime imaging of G4 RNA in living cells. Structural modifications of thiazole orange enhance RNA-binding affinity and G4 selectivity. TOGR exhibits a unique fluorescence lifetime when bound to G4 structures, enabling sensitive detection of G4 formation independent of local probe concentration via FLIM. FLIM imaging reveals that TOGR primarily colocalizes with RNA in the cytoplasm and nucleoli. Due to its preferential RNA-binding affinity in competitive cellular environments, TOGR enables selective monitoring of G4 RNA dynamics, facilitating the exploration of novel roles of G4 RNA in cells without interference from G4 DNA. Importantly, the dynamic behavior of G4 RNA during Alzheimer's disease pathology and the effects of glucocorticoids on G4 RNA dynamics were successfully revealed using this lifetime-sensitive and RNA-selective imaging probe. This research not only paves the way for advanced probe design for detailed G4 RNA imaging but also lays the foundation for exploring G4 RNA-related pathological mechanisms in Alzheimer's disease.},
}

@article {pmid42508392,
year = {2026},
author = {Kumar, V and Jang, S and Choi, Y and Kim, S and Nam, Y and You, M and Moon, M},
title = {Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0606},
pmid = {42508392},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.},
}

@article {pmid42509698,
year = {2026},
author = {Wang, X and Li, J and Wei, Z and Rong, C and Zhao, D and Wang, Y},
title = {Integrating Multi-Omics and Mendelian Randomization Reveals the Role of Epstein-Barr Virus Infection in Alzheimer's Disease and the Therapeutic Potential of Resveratrol.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050463115260708111634},
pmid = {42509698},
issn = {1875-5828},
abstract = {INTRODUCTION: The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs.

MATERIALS AND METHODS: Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation.

RESULT: Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2.

DISCUSSION: This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally.

CONCLUSION: This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.},
}

@article {pmid42509706,
year = {2026},
author = {Shen, Z and Cheng, J and Wang, L and Hou, Q},
title = {Molecular Mechanisms and Therapeutic Strategies in Parkinson's Disease: From Pathogenic Signaling to Drug Development.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457429260706102249},
pmid = {42509706},
issn = {1875-6190},
abstract = {Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD), yet no effective disease-modifying therapy is currently available. Its pathogenesis is highly complex, involving multiple interacting pathological processes, which poses substantial challenges for therapeutic intervention. Moreover, PD often has a prolonged prodromal phase and lacks sufficiently sensitive and specific diagnostic methods for early-stage detection, further limiting timely identification and treatment. Current pharmacological therapies mainly provide symptomatic relief, but their long-term use is frequently associated with reduced efficacy and motor complications. Therefore, the development of novel therapeutic strategies and potential disease-modifying agents remains an urgent priority. This review systematically summarizes the molecular mechanisms and biomarkers associated with PD, outlines current symptomatic treatments, and discusses emerging therapeutic candidates in clinical development, with particular emphasis on disease-modifying strategies. By integrating pathogenic mechanisms, diagnostic advances, and therapeutic progress, this review aims to provide a comprehensive perspective to support the development of more effective interventions for PD.},
}

@article {pmid42509708,
year = {2026},
author = {Liu, Y and Zhang, Y and Zheng, W and Shi, X and Yao, W and Zhang, J and Bai, F},
title = {Cortico-white Matter Functional Coupling as a Biomarker of Alzheimer's Disease Progression and rTMS Therapeutic Efficacy.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X470892260706231913},
pmid = {42509708},
issn = {1875-6190},
abstract = {INTRODUCTION: Alzheimer's disease (AD) spectrum disorders are characterized by progressive cognitive decline, with white matter degeneration and disrupted cortico-cortical connectivity as early features. Cortico-white matter functional coupling integrates neuronal activity with axonal conduction, yet its natural trajectory across the AD spectrum and ability to be modulated by repetitive transcranial magnetic stimulation (rTMS) remain unclear.

METHODS: Longitudinal resting-state fMRI from the ADNI cohort (n = 160: 59 cognitively normal, CN; 65 mild cognitive impairment, MCI; 36 AD) was used to assess baseline and 1-year changes in mean Fisher's z-transformed coupling between 82 cortical seeds (AAL-90 atlas, excluding subcortical nuclei) and a probabilistic group white matter mask. Specifically, 54 patients with amnestic MCI (aMCI) from the rTMS cohort were allocated to active (n = 40) or sham (n = 14) groups and received four weeks of neuronavigated rTMS targeting the left angular gyrus. Cortico-white matter functional coupling was calculated identically in both cohorts. Changes in coupling strength and their associations with changes in neuropsychological performance were examined across all cortical seeds.

RESULTS: At baseline, mean cortico-white matter functional coupling followed a nonlinear pattern (MCI > AD and CN). One-year follow-up revealed that the CN group exhibited a slight decrease in coupling, and the MCI and AD groups showed a pathological increase. Compared with the sham group, active rTMS significantly attenuated this increase in coupling. After adjusting for covariates, coupling changes were strongly correlated with cognitive decline. The AD group demonstrated the most significant associations (n = 104), whereas the active rTMS group showed 71 associations, predominantly linked to objective memory improvement.

DISCUSSION: This abnormal overcoupling, leading to compensation and decompensation, is associated with the progression of Alzheimer's disease. rTMS effectively moderates this pathological surge by enhancing neural efficiency and stabilizing large-scale network integration. Our findings position cortico-white matter functional coupling as an effective indicator of disease intensity and a measurable link in the chain of rTMS effectiveness for early-stage AD.

CONCLUSION: Overall, cortico-white matter functional coupling may serve as a novel scan-based biomarker for tracking AD progression and evaluating rTMS treatment efficacy in patients with MCI.},
}

@article {pmid42509854,
year = {2026},
author = {Alessio, M and Giulia, N and Annagrazia, A and Francesco, A and Raffaele, M and Massimo, C and Giacinto, B and Carlo, N and Romano, E and Rossella, R},
title = {Lithium as a Potential Neuroprotective Strategy in Glaucoma: Mechanisms and Therapeutic Perspectives.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071062},
pmid = {42509854},
issn = {2218-273X},
abstract = {Glaucoma is a major global health concern, identified as the foremost cause of irreversible blindness, affecting nearly 95 million individuals. It is characterized by the progressive degeneration of retinal ganglion cells (RGCs), leading to significant vision-related disabilities and an extensive socio-economic impact. The concept that glaucoma should be viewed not solely as an ocular condition but also as a neurodegenerative disorder, sharing pathophysiological features with diseases like Alzheimer's and Parkinson's, is now widely accepted. This review examines the convergence of molecular mechanisms, including the roles of amyloid precursor proteins and neuroinflammation, that contribute to RGC loss. Notably, lithium, traditionally used as a mood stabilizer, has emerged as a potential neuroprotective agent for the treatment of Alzheimer's disease. In light of the common neurodegenerative mechanisms linking glaucoma with central neurodegenerative diseases, here, we review the current evidence supporting lithium's therapeutic potential in glaucoma, emphasizing the need for further clinical studies to determine its effectiveness in preserving optic nerve health and improving patient outcomes.},
}

@article {pmid42510665,
year = {2026},
author = {Mitroshina, EV and Strelkova, PL and Korokozova, MV and Vedunova, MV},
title = {HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141118},
pmid = {42510665},
issn = {2079-7737},
support = {22-15-00178-p//Russian Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide and is characterized by progressive memory impairment, cognitive decline, and behavioral dysfunction. The brain's high energy demand makes it vulnerable to hypoxia, which can trigger AD pathology. Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular and tissue adaptation to low oxygen levels. HIF-1 plays a dual role in AD: on the one hand, it is considered a potential neuroprotective target; on the other hand, its activation may exacerbate disease pathogenesis by promoting amyloid plaque formation. Given this ambiguity, further studies are needed. This study investigated the HIF prolyl hydroxylase inhibitor Roxadustat in 6-month-old male 5xFAD mice. Stabilization of the HIF-1 complex exerted a positive effect on learning ability and the retention of long-term spatial memory in 6-month-old male 5xFAD mice. Four-week treatment with Roxadustat significantly reduced pathological morphological alterations in cells of the prefrontal cortex. In addition, animals treated with Roxadustat exhibited significantly increased expression of the brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Our findings suggest that stabilization of the HIF-1 complex through inhibition of HIF prolyl hydroxylase may represent a promising strategy for neuroprotection in AD.},
}

@article {pmid42510722,
year = {2026},
author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C},
title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141176},
pmid = {42510722},
issn = {2079-7737},
abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.},
}

@article {pmid42511504,
year = {2026},
author = {Post, WM and Widomska, J and Oosterwijk, E and De Witte, W and Tiemessen, DM and Klemann, CJHM and Ruisch, IH and Coenen, MJH and Janssen, DAW and Martens, F and Carnes, MU and Marks, JA and Page, GP and Richter, HE and Cartwright, R and Minassian, VA and Thomas, LF and Skogholt, AH and Stafne, SN and Hveem, K and Kluivers, KB and Poelmans, G},
title = {Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511504},
issn = {1422-0067},
support = {PROJ00787 (DIABIP)//European Fund for Regional Development (EFRD)/ ; },
abstract = {Urgency urinary incontinence (UUI) and Alzheimer's disease (AD) are highly comorbid conditions in women, but the underlying molecular mechanisms are largely unknown. Therefore, we used network enrichment analyses and an elaborate literature search to integrate the most significant genes from four genome-wide association studies (GWASs) and other genetic, expression and functional evidence into a molecular landscape of female UUI. This molecular landscape centers around local, i.e., bladder-based, processing of the AD-associated amyloid precursor protein (APP). To further elucidate how APP processing is implicated in the comorbidity between UUI and AD, we conducted polygenic risk score (PRS)-based analyses, which showed that genetic risk factors associated with AD and a decreased amyloid beta 42/40 blood level ratio (also) contribute to UUI susceptibility. In conclusion, APP processing constitutes a putative molecular link between UUI and AD, adding further weight to their clinical comorbidity and having implications for the treatment (and prevention) of both traits.},
}

@article {pmid42512037,
year = {2026},
author = {Bagda, V and Farooz, ZH and Knuckey, NW and South, SM and Gribble, SK and Tomar, M and Bharadwaj, P and Ariyath, A and Taddei, K and Martins, RN and Meloni, BP},
title = {The Poly-Arginine Peptide R18D Inhibits Amyloid-Beta (Aβ) Aggregation and Aβ-Induced Cytotoxicity, Reduces Intracellular Tau Aggregation, and Exhibits Oral Bioavailability.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071564},
pmid = {42512037},
issn = {2227-9059},
support = {N/A//Perron Institute for Neurological and Translational Science/ ; N/A//Argenica Therapeutics/ ; },
abstract = {Background/Objectives: Effective disease-modifying therapies targeting pathogenic proteins associated with Alzheimer's disease (AD) remain limited. This study investigated the therapeutic potential of the neuroprotective, cationic arginine-rich peptide R18D to mitigate the pathogenic effects of amyloid-beta (Aβ) and tau associated with AD. Methods: R18D was examined for its ability to inhibit Aβ aggregation in a cell-free assay, attenuate Aβ-induced cytotoxicity in MC65 cells, and suppress intracellular tau aggregation in two neural cell models. Intracellular tau aggregation was quantified using a homogeneous time-resolved fluorescence assay. Additionally, a pilot pharmacokinetic study of R18D was conducted in mice following oral gavage administration. Results: In the cell-free assay, R18D inhibited Aβ aggregation by up to 65%. In human MC65 cells induced to overexpress APP-C99 and accumulate Aβ, treatment with R18D inhibited cellular toxicity by as much as 100%. Preformed tau seeds were applied to human SH-SY5Y cells and rat primary cortical neurons to induce intracellular tau aggregation, and tau levels were quantified after 48 h. Exposure to tau seeds induced robust tau aggregation in both cellular models, which was significantly attenuated by R18D treatment, reducing aggregation by 34.8% in SH-SY5Y cells and 49.9% in cortical neurons. Pharmacokinetic studies demonstrated that R18D was detectable in plasma at 30 and 60 min following oral administration in mice. Conclusions: Together, these results demonstrate that R18D can modulate both Aβ and tau pathologies in vitro and is orally bioavailable, supporting its further evaluation as a therapeutic candidate for AD and other tau-associated neurodegenerative disorders.},
}

@article {pmid42512450,
year = {2026},
author = {Yogi, S and Singh, A},
title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070675},
pmid = {42512450},
issn = {2076-3425},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.},
}

@article {pmid42512462,
year = {2026},
author = {Siarkos, K and Politis, AM and Politis, AA and Smyrnis, N and Papageorgiou, C and Prentakis, A and Gournellis, R and Katirtzoglou, E and Theleritis, C},
title = {Non-Pharmacological Interventions for Managing Apathy in Older Adults with Neurocognitive Disorders: A Systematic Review of Randomized Controlled Trials.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070687},
pmid = {42512462},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Apathy is among the most common neuropsychiatric features of late-life neurocognitive disorders and predicts functional decline and greater caregiver burden. As no treatment is formally established, identifying effective interventions is a priority. We systematically reviewed non-pharmacological randomized controlled trials (RCTs) targeting apathy in older adults with neurocognitive disorders.

METHODS: We searched PubMed/MEDLINE, PsycInfo, the Cochrane Library, and Google Scholar (final search 23 March 2026). Eligible studies were non-pharmacological RCTs reporting an apathy outcome. Evidence levels were graded with OCEBM and quality with PEDro; two reviewers mapped PEDro items onto Cochrane risk-of-bias domains. Reporting followed PRISMA 2020.

RESULTS: Sixty-two RCTs were included. Physical exercise and music-based interventions showed the most consistent benefit, whereas technology-based and brain stimulation approaches remained experimental. Only 30 trials (48%) showed a significant between-group effect on apathy-most were null, within-group, or had apathy as a secondary outcome. Marked heterogeneity precluded meta-analysis. Most trials were of moderate to high quality, though near-universal performance bias arose from the inability to blind participants and providers.

CONCLUSIONS: Managing apathy in these populations remains challenging, and the certainty of the evidence is limited. Purpose-built, apathy-focused trials reporting effect sizes and durability are needed before disease-specific recommendations can be made.},
}

@article {pmid42512531,
year = {2026},
author = {Phutirat, A and Culevski, KA and Mach, H and Kwon, J and Tan, H and Koh, G and Marzban, C and Mourad, PD},
title = {Low-Intensity Focused Ultrasound Alters Alzheimer's Disease Pathology, In Vivo, as a Function of Ultrasound Dose and Age.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070757},
pmid = {42512531},
issn = {2076-3425},
support = {W81XWH-20-1-0479//Congressionally Directed Medical Research Programs/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's Disease (AD) and vascular dementia contribute up to ~75% of dementia cases, as determined via autopsy. AD arises in part due to the buildup of aberrant proteins (amyloid beta (Aβ) and Tau); vascular dementia is caused by reduced cerebral blood flow. Each dementia mechanisms damages brain. Bobola et al. found that their low-intensity focused ultrasound (FUS) protocol applied to the brains of the 5XFAD mouse model of AD reduced Aβ by 50% through activation of microglia. Eguchi et al. found that their own FUS protocol applied to the brains of the same mouse model reduced Aβ by 15% and increased cerebral blood flow by 50% through an increase in endothelial nitric oxide synthase (eNOS). Here, we sought to test a combined version of those two FUS protocols, expecting both a decrease in Aβ burden and an increase in eNOS.

METHODS: Using a diagnostic ultrasound probe, we applied our combined FUS protocol primarily to the left hippocampus of anesthetized 5XFAD mice, for an hour a day, for three days for younger mice and for five days for older mice. On day three or five, respectively, we harvested their brains and performed histological analysis to assess Aβ burden, microglial activation and their co-localization with Aβ, as well as the burden of eNOS within neuronal nuclei (here called intra-neuronal eNOS) and outside of neurons.

RESULTS: Relative to untreated mice, the treated younger mice had more activated microglia co-localized with Aβ and reduced Aβ burden for large plaques, as well as no change in each measure of eNOS. In contrast, the treated older AD mice had no change in activated microglia co-localized with Aβ, and no change in Aβ burden. However, relative to untreated older AD mice, FUS decreased total and extra-neuronal eNOS and increased intra-neuronal eNOS.

CONCLUSIONS: The ability of our FUS protocol to reduce Aβ burden and alter the eNOS distribution depends critically upon the age of the AD mice (more Aβ plaques for a comparable number of microglia for older mice relative to younger mice) and duration of the treatment. The observed decrease in extra-neuronal eNOS distribution in older AD mice caused by FUS raises the concern that our protocol may increase ischemia, while the increase in intra-neuronal eNOS may counteract that effect via protection of synaptic function. These findings also identify two candidate therapeutic windows for our FUS treatment protocol, each requiring more research before translation to humans. One window is early intervention to maximize Aβ plaque removal via activation of microglia. The second is later intervention to protect synaptic function if it is possible to mitigate the potential ischemic risk caused by the differential effects of FUS on eNOS.},
}

@article {pmid42512898,
year = {2026},
author = {Kannenieks, D and Priede, Z and Millers, A and Velins, KK},
title = {Development and External Validation of a Machine Learning Model for Classification of Mild Cognitive Impairment and Dementia Using Clinical Data.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {7},
pages = {},
doi = {10.3390/medicina62071356},
pmid = {42512898},
issn = {1648-9144},
abstract = {Background and Objectives: As society ages, the number of patients with cognitive impairment is increasing. Machine learning methods that use structured clinical and cognitive-assessment data during routine diagnostic work-up may support and monitor structured classifications of cognitive status. This kind of approach can improve early screening, reduce physicians' workload and develop greater support for personalized treatment. To develop an XGBoost-based machine learning model using the National Alzheimer's Coordinating Center (NACC) dataset and to evaluate the model's precision with clinician-assigned diagnosis in a Latvian retrospective cohort study. Materials and Methods: The research was designed as a retrospective external validation cohort study that used two data sources. Firstly, the National Alzheimer's Coordination Center (NACC) longitudinal dataset was used to train the ML model. Secondly, medical records gathered from Pauls Stradins Clinical University Hospital dating from 2020 to May 2025 were used to evaluate the algorithm's precision. Results: In the NACC study, the weighted four-class model achieved an overall accuracy of 84.0% and a balanced accuracy of 70.9%, but the SCD class remained poorly classified. After reframing the model to a three-class model the performance grew stronger for normal cognition, mild cognitive impairment (MCI) and dementia. Class distribution in the Latvian cohort consisted of dementia (n = 138); MCI (n = 13); and subjective cognitive decline (SCD) (n = 2). Dementia was identified most strongly-124/138 (sensitivity-89.9%). MCI was correct in 9/13 cases (sensitivity-69.2%). SCD cases were excluded. Overall, the model agreed with the neurologist-assigned diagnoses in 88.1% of the cases (133/151). Conclusions: The ML classification model has high precision when comparing with neurologist-assigned diagnoses, but it struggles to separate adjacent early-stage diagnoses, meaning that it did not reliably identify SCD. These findings support further methodological development and the implementation of prospective research. Nevertheless, this technology has high potential for being integrated in the future to aid triage and early screening, especially when advanced diagnostics are limited.},
}

@article {pmid42513614,
year = {2026},
author = {Çetinkaya, K and Ünsal, Y},
title = {The Glymphatic System and Neurosurgery: A Comprehensive Narrative Review of Current Concepts and Future Directions.},
journal = {Journal of clinical medicine},
volume = {15},
number = {14},
pages = {},
pmid = {42513614},
issn = {2077-0383},
abstract = {The glymphatic system is a recently defined perivascular waste elimination pathway responsible for the efficient clearance of metabolic waste and neurotoxic proteins in the central nervous system. This system facilitates the entry of cerebrospinal fluid (CSF) into the brain parenchyma via arterial perivascular spaces and its interaction with interstitial fluid (ISF) via glial cell-associated aquaporin-4 (AQP4) channels. It functions particularly actively during sleep. Impairment of glymphatic flow contributes to nerve cell damage and neuroinflammation in various pathologies such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, subarachnoid hemorrhage, and neurological tumors. In neurosurgical practice, surgical positioning, anesthesia regimen, and intracranial pressure changes play a decisive role in glymphatic function, and perioperative modulation of the system can affect postoperative recovery and cognitive outcomes. Today, non-invasive imaging techniques and molecular biological approaches are deepening our understanding of the functioning of the glymphatic system in humans, and this system is emerging as a potential target in the diagnosis and treatment of neurological diseases. This review comprehensively addresses the basic anatomical and physiological principles of the glymphatic system, its role in pathological processes, and its clinical significance in neurosurgical applications.},
}

@article {pmid42514879,
year = {2026},
author = {Osmanlioglu Dag, SR and Alagoz, MA},
title = {Dual Targeting of AChE Inhibition and GPX4 Binding by Plant-Derived Compounds for the Treatment of Alzheimer's Disease: Insights from Molecular Docking and Molecular Dynamics Simulations.},
journal = {Pharmaceutics},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/pharmaceutics18070798},
pmid = {42514879},
issn = {1999-4923},
support = {TSA-2025-4366.//Inonu University/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is primarily characterized by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains the mainstay of symptomatic treatment. However, additional hypotheses such as ferroptosis-an iron-dependent form of regulated cell death-have gained prominence in explaining disease progression. Glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme, plays a protective role by suppressing ferroptotic pathways. In this context, identifying phytochemicals capable of inhibiting AChE and exhibiting activator-like binding toward GPX4 may provide a dual therapeutic benefit. This study aimed to identify such dual-acting compounds through a structure-based virtual screening approach. Methods: A total of 3014 natural compounds were collected from three curated databases: NPACT, HIT, and HIM. Molecular docking was performed against GPX4 (7U4I) and AChE (7D9Q). Compounds demonstrating high affinity for both targets were shortlisted. Z-score normalization and statistical ranking were used to select the best two dual-target compounds. Results: Out of 3014 compounds, 68 showed dual-binding potential. Among these, NPACT00189 (docking scores: -6.720 kcal/mol for GPX4; -8.983 kcal/mol for AChE) and NPACT01210 (docking scores: -5.813 kcal/mol for GPX4; -9.640 kcal/mol for AChE) were identified as top candidates based on docking scores. Molecular dynamics (MD) simulations were conducted for both compounds for 250 ns on the AChE binding site and the allosteric site of GPX4. The results indicated that NPACT00189 maintained stable interactions throughout the simulation period at both targets, indicating its dual-targeting potential. Conclusions: NPACT00189 represents a promising dual-target candidate for further investigation in AD therapy. Its potential requires confirmation through comprehensive in vitro and in vivo studies.},
}

@article {pmid42514962,
year = {2026},
author = {Chen, C and Leung, C and Zhai, Z and Wang, G and Yang, R and Hu, Q and Yue, X and Yao, Z and Zhao, Z and Zhang, X},
title = {Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer's Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy.},
journal = {Pharmaceutics},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/pharmaceutics18070885},
pmid = {42514962},
issn = {1999-4923},
support = {2025A1515010639//Natural Science Foundation of Guangdong Province/ ; },
abstract = {Background: Alzheimer's disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood-brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P3 achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P0. Subsequent in vivo biodistribution studies showed that P3 produced higher brain drug exposure than both intranasally administered P0 and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases.},
}

@article {pmid42515707,
year = {2026},
author = {Mella, J and Vega-Muñoz, A and Soto, M and Moraga, D and Campanini-Salinas, J and Sandoval-Obando, E and Contreras-Barraza, N and Salazar-Sepúlveda, G and Salas-Guzmán, N and Carabantes-Silva, R and Mellado, M},
title = {Evolution of Multitarget Strategies for Alzheimer's Disease: From Cholinergic Inhibition to Network-Oriented Therapeutic Design (2006-2025).},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071024},
pmid = {42515707},
issn = {1424-8247},
support = {Puente de Investigación UCEN Convocatoria Año 2025 grant CIPPTE202505//Central University of Chile/ ; },
abstract = {Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional "one drug-one target" paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood-brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design.},
}

@article {pmid42515891,
year = {2026},
author = {Jia, J},
title = {Glycogen Synthase Kinase-3β in Alzheimer's Disease: Targets for Therapy and Imaging.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266497019260720045602},
pmid = {42515891},
issn = {1873-4294},
abstract = {Glycogen synthase kinase-3β (GSK-3β) is a key regulator of the pathogenesis of Alzheimer's disease (AD), capable of simultaneously modulating core pathological processes such as amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, synaptic damage, and neuroinflammation. Therefore, it has become one of the core druggable molecular nodes for AD intervention. This review is mainly divided into two parts. The first part focuses on the GSK-3β inhibitors that have been validated in AD-related cell and animal models. These inhibitors are specifically classified into four categories: metal ion-based compounds, adenosine triphosphate (ATP)-competitive inhibitors, non-ATP-competitive inhibitors, and multi-target inhibitors. The second part focuses on GSK-3β-specific positron emission tomography (PET) radioligands, which can non-invasively monitor GSK-3β enzyme activity in vivo, providing quantitative in vivo molecular imaging tracers for the study of AD pathogenesis and quantitative assessment of treatment effects. This review systematically summarizes GSK-3β-related inhibitors and PET radioligands in AD, thereby providing key references for the rational design of next-generation AD therapeutic drugs and diagnostic agents.},
}

@article {pmid42515916,
year = {2026},
author = {Saini, M and Hooda, T and Dar, MO and Kumar, S and Khatri, R and Lather, A},
title = {Network Pharmacology-guided Target Evaluation of Nefopam for Alzheimer's Disease: Insights from Docking and Molecular Dynamics Simulations.},
journal = {Current computer-aided drug design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734099474093260712091739},
pmid = {42515916},
issn = {1875-6697},
abstract = {INTRODUCTION: Amyloid-β accumulation, aberrant tau protein, neuroinflammation, and oxidative stress are some of the main pathogenic characteristics of Alzheimer's disease (AD), a degenerative illness characterized by cognitive deterioration. The majority of current AD therapies provide symptomatic alleviation with significant adverse effects, highlighting the urgent need for novel therapeutic approaches.

OBJECTIVE: This study examines nefopam, a centrally acting analgesic with NMDA antagonist and monoaminergic properties, as a potential treatment for AD using in silico methods like Network Pharmacology, Docking, and Molecular Dynamics Simulation studies.

RESULTS: Using network pharmacology, 90 molecular targets shared by the AD and nefopam pathways were identified. Following the selection of important hub proteins for further analysis, eight proteins with accessible 3D structures were put through molecular docking and MMGBSA computations. Nefopam demonstrated significant binding affinities, especially to 5HTR2A, GRIN1, 5HTR2C, SLC6A4, SLC6A3, and MAOB, whereas OPRM1 displayed weaker interactions, consistent with its lower MM-GBSA value (-37.04 kcal/mol) and docking score (-2.963). Molecular dynamics simulations of particular complexes over 100 ns revealed stable contacts and minimal structural changes for SLC6A3, SLC6A4, and 5HTR2A, suggesting strong and long-lasting binding.

DISCUSSION: The findings suggest that nefopam exhibits significant multi-target interactions with several proteins involved in AD pathogenesis, particularly those associated with neurotransmission, neuroprotection, and neuroinflammatory pathways. Its stable binding behavior and favorable interaction profiles support its potential role in modulating disease progression beyond symptomatic management.

CONCLUSION: Overall, this computational analysis confirms that nefopam can target multiple proteins linked to AD. These results show that more experimental research is necessary to validate nefopam's therapeutic potential and provide positive support for its repositioning in AD treatment.},
}

@article {pmid42516031,
year = {2026},
author = {Snyder, HM and Tampi, MP and Aisen, PS and Allegri, R and Apostolova, LG and Atri, A and Aurora, S and Caramelli, P and Crivelli, L and Cummings, J and de Strooper, B and Fox, NC and Grinberg, LT and Hardy, J and Lamb, BT and Levey, A and Lopez, O and Mummery, C and Nitrini, R and Pahlke, S and Petersen, RC and Pike, KJ and Porsteinsson, AP and Rabinovici, GD and Rafii, M and Raman, R and Sabbagh, MN and Salloway, SP and Scheltens, P and Schott, JM and Selkoe, DJ and Sevlever, G and Sperling, R and Tansey, MG and van Dyck, C and Zetterberg, H and Carrillo, MC},
title = {Recent Cochrane review has serious flaws: A perspective of clinicians and researchers from around the world.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71696},
pmid = {42516031},
issn = {1552-5279},
abstract = {In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject-matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence-synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment-specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.},
}

@article {pmid42516875,
year = {2026},
author = {Tropea, MR and Aceto, G and Trovato, RC and Nicitra, E and Santuccio, N and Intili, G and D'Ascenzo, M and Puzzo, D},
title = {Dopamine D3 receptor blockade restores hippocampal synaptic plasticity and rescues memory deficits in Alzheimer's disease mouse models.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1840697},
pmid = {42516875},
issn = {1663-4365},
abstract = {INTRODUCTION: Early synaptic failure is widely considered a primary driver of cognitive decline in Alzheimer's disease (AD), and previous studies have suggested that dopaminergic signaling may contribute to hippocampal synaptic dysfunction. Among dopaminergic receptors, dopamine D3 receptors (D3Rs) have emerged as important modulators of synaptic plasticity and cognitive processes, but their role in AD-related synaptic impairment remains unclear. The aim of this study was to determine whether pharmacological blockade of D3Rs could restore memory deficits and hippocampal synaptic dysfunction in preclinical models of AD.

METHODS: Behavioral studies, including novel object recognition (NOR), novel object location (NOL), and open-field tests, were performed to evaluate recognition memory, spatial memory, locomotor activity, and anxiety-related behavior in two mechanistically distinct mouse models of AD: triple-transgenic 3xTg-AD mice and α7 nicotinic acetylcholine receptor knockout (α7KO) mice. Electrophysiological recordings in hippocampal slices were used to assess AMPA/NMDA ratio, basal synaptic transmission, and long-term potentiation (LTP). qPCR and western blot analyses were performed to evaluate hippocampal D3R mRNA and protein expression, respectively. Pharmacological treatments included the selective D3R antagonist NGB-2904 and cariprazine, a clinically approved antipsychotic with high affinity for D3Rs.

RESULTS: Recognition and spatial memory deficits were rescued by NGB-2904 and cariprazine in both AD models, without affecting locomotor activity or anxiety-related behavior. No sex-dependent differences were observed in the behavioral response to treatment. Electrophysiological recordings revealed a reduced AMPA/NMDA ratio and impaired LTP in both models, while basal synaptic transmission was selectively reduced in 3xTg-AD mice. D3R-targeting compounds restored synaptic transmission and plasticity. Inhibition of PKA prevented the rescue of LTP induced by D3R blockade, suggesting the involvement of the cAMP/PKA signaling pathway. Both models displayed reduced hippocampal D3R mRNA expression and protein levels, suggesting that the residual population of D3Rs might represent a viable target.

CONCLUSION: Together, these findings demonstrate that D3R-targeting compounds rescue synaptic plasticity and memory deficits in two mechanistically distinct AD models. These results support a role for dopaminergic signaling in early synaptic dysfunction and highlights D3R modulation as a relevant pathway for further investigation in AD-related cognitive impairment.},
}

@article {pmid42517615,
year = {2026},
author = {Ya, J and Liu, M and Ji, Y and Tong, Z and Luo, B and Bai, J and Ren, J and Qu, X},
title = {Diazonium-Enabled Post-Synthetic Construction of Enantiomeric Single-Atom Nanoagents Used for Alzheimer's Disease Treatment.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e74610},
doi = {10.1002/smll.74610},
pmid = {42517615},
issn = {1613-6829},
support = {T2495262//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; 2025ZD0617100//National Science and Technology Major Project/ ; },
abstract = {Alzheimer's disease (AD) is driven by a self-amplifying interplay between oxidative stress and neuroinflammation, in which mitochondrial DNA (mtDNA) leakage-induced activation of the cGAS-STING pathway plays a central role. Strategies that solely eliminate reactive oxygen species (ROS) are insufficient to suppress downstream inflammatory cascades. Here, we report a pair of chiral dual-functional single-atom nanoagents that can simultaneously scavenge ROS and sequester leaked mtDNA. A diazonium-enabled post-synthetic modification strategy is employed to graft benzoic acid linkers onto a single-atom catalyst, enabling covalent conjugation of nona-arginine peptides with opposite chirality (L-/D-R9). The resulting constructs are further encapsulated by KLVFFAED peptides and tannic acid to yield L-/D-TKRM, conferring blood-brain barrier permeability and mitochondrial targeting. Both L- and D-TKRM effectively scavenge ROS and preserve mitochondrial function in Aβ-stimulated microglia, while D-TKRM exhibits enantioselectively prolonged mtDNA capture, more efficient suppression of cGAS-STING signaling, enhanced M2 microglial polarization, and superior neuroprotection. In vivo studies have demonstrated that these two nanoagents rescue cognitive function in 3 × Tg-AD mice, with D-TKRM showing better efficacy accompanied by reduced amyloid pathology, microglial activation, and neuronal loss. This work highlights diazonium chemistry as a new, versatile single-atom functionalization strategy and underscores that chirality is important for developing effective therapeutic agents for AD treatment.},
}

@article {pmid42498697,
year = {2026},
author = {Makhaeva, GF and Astakhova, TY and Grishchenko, MV and Shteinberg, TS and Kovaleva, NV and Boltneva, NP and Rudakova, EV and Pronkin, PG and Timokhina, EN and Radchenko, EV and Shchegolkov, EV and Burgart, YV and Saloutin, VI and Charushin, VN and Richardson, RJ},
title = {Influence of N-Functionalization of Amiridine on the Biological Activity of Its Conjugates as Multitarget Agents for Potential Treatment of Alzheimer's Disease.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70392},
pmid = {42498697},
issn = {1860-7187},
support = {24-63-00016//Russian Science Foundations/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Humans ; Peptide Fragments/metabolism/antagonists & inhibitors ; Structure-Activity Relationship ; Molecular Structure ; Molecular Docking Simulation ; Imines/chemistry ; },
abstract = {The goal of this mechanistic study was to elucidate the influence of N-functionalization of amiridine on the biological properties of its conjugates. We synthesized conjugates of amiridine and salicylimine/amine 9, 10 with linkers containing an N-acyl group at the amiridine fragment as analogs of our previously obtained hybrids 1, 2 containing an N-aminohexamethylene spacer. A comparative study of selected biological activities of N-acylalkylene conjugates 9, 10 with conjugates 1, 2 showed substantial decreases in anti-butyrylcholinesterase (BChE) activity (35-fold for the imine and 8-fold for the amine), loss of anti-acetylcholinesterase (AChE) activity, and disappearance of the ability to block amyloid beta (1-42) (Aβ42) self-aggregation. Similar effects were observed for the model compound N-hexylamiridine 3 and its N-acyl derivative 11. However, N-acyl functionalization at the amiridine pharmacophore did not reduce the ability of the conjugates to block AChE-induced β-amyloid aggregation and only slightly decreased their antiradical activity, maintaining the higher activity of amines compared to imines. These effects were consistent with results from quantum mechanical calculations and molecular docking, showing that N-acylation of amiridine decreased the proton affinity of its endocyclic N-atom. Consequently, the amiridine pharmacophore was essentially unprotonated, thereby diminishing the anticholinesterase activity of conjugates 9 and 10 and their ability to block Aβ42 self-aggregation.},
}

*Alzheimer Disease/drug therapy/metabolism
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Humans
Peptide Fragments/metabolism/antagonists & inhibitors
Structure-Activity Relationship
Molecular Structure
Molecular Docking Simulation
Imines/chemistry

@article {pmid42498936,
year = {2026},
author = {Poffenberger, CN and Taylor, MM and Larson, K and Mufson, EJ and Dixon, KJ},
title = {Inhibition of Soluble TNF Mitigates Traumatic Brain Injury as a Risk Factor for the Development of Amyloidogenic Proteins and Functional Deficits in 3xTg-AD Mice.},
journal = {Journal of neurotrauma},
volume = {},
number = {},
pages = {8977151261469044},
doi = {10.1177/08977151261469044},
pmid = {42498936},
issn = {1557-9042},
abstract = {Traumatic brain injury (TBI) is a well-known risk factor for dementia with Alzheimer's disease (AD), and there are no known therapies that can mitigate this risk. Pre-clinical studies demonstrate a temporary upregulation of amyloid beta (Aβ) and corresponding neurological dysfunction following TBI with little-to-no studies developing interventions to prevent this pathophysiology. The pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to promote the development of AD, and here we investigate whether a clinically relevant biologic known as XPro1595 that neutralizes soluble TNF (solTNF) can mitigate TBI as a risk factor for the development of amyloidogenic proteins and corresponding neurological dysfunction. Following a single controlled cortical impact model of TBI or sham-injury, adult male 3xTg-AD mice were treated acutely with either XPro1595, a dominant-negative protein that neutralizes soluble TNF (10 mg/kg, S.C.), or vehicle solution. Between 6 h and 1 month post-injury (MPI), levels of cytokines, inflammatory markers, and AD-related proteins were evaluated in the ipsilateral hippocampus. Additionally, animals were behaviorally tested for deficits in cognition (learning and memory), as well as hindpaw mechanical hypersensitivity. TBI induced a significant increase in TNF (ELISA, 6 h) and TNFR1 (Western blot, 3 days post-injury [DPI]) expression, which correlated with an increase in BACE1, Aβ42, and caspase-3 at 3 and 7 DPI. Significant deficits in cognition and mechanical hypersensitivity were found at 7 DPI with similar trends at 1 MPI. In comparison, injured mice treated with XPro1595 had improvements in cognition and mechanical hypersensitivity (cf. vehicle-treated injured mice) and did not have these same increases in BACE1, Aβ42, and caspase-3 (levels were similar to sham-injured mice), likely by increasing NF-κB deactivation (pNF-κB [p65; Ser468]), indicative of a reduced inflammatory response. Overall, treatment with XPro1595 following TBI prevented the development of amyloidogenic proteins and corresponding neurological dysfunction. Clinically, these data support the use of XPro1595 as a clinically relevant therapeutic for patients with TBI to mitigate the risk of increased Aβ levels and neurological decline subacutely post-injury.},
}

@article {pmid42499341,
year = {2026},
author = {Singh, B and Pigazzani, F and Manfredini, R},
title = {Circadian rhythms and chronotherapy in Alzheimer's disease: Mechanisms and therapeutic implications.},
journal = {Neuroprotection (Chichester, England)},
volume = {},
number = {},
pages = {},
pmid = {42499341},
issn = {2770-730X},
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, has been increasingly associated with disruptions in circadian rhythms and sleep-wake regulation. This narrative review synthesizes recent literature on how circadian dysfunction may contribute to AD pathogenesis, biomarker profiles, and treatment response. Mechanistic studies suggest important interactions between core clock genes and neurodegenerative cascades involving oxidative stress, neuroinflammation, glial reactivity, and proteostasis. Disruptions in circadian-regulated molecular pathways, including brain and muscle ARNT-like 1 (BMAL1)-sirtuin 1 (SIRT1), nuclear factor kappa B (NF-κB)-NOD-like receptor family pyrin domain containing 3 (NLRP3), and period circadian regulator 2 (PER2)-antioxidant signaling pathways, may compromise neuronal resilience and worsen AD-related pathology. Emerging evidence also suggests distinct circadian patterns in AD-relevant biomarkers, including melatonin, cortisol, orexin, core body temperature, blood-brain barrier permeability, and glial marker oscillations. These rhythmic patterns may have diagnostic and prognostic relevance and support the need for time-aware biomarker interpretation. Chronotherapeutic strategies targeting circadian biology, including melatonin receptor agonists, light therapy, time-restricted feeding, and circadian-aligned drug delivery systems, may help improve targeted clinical endpoints in AD. This review also discusses chronoepigenetics as an emerging area in which clock-regulated epigenetic modifications may influence neurodegenerative trajectories. Future directions include next-generation chronotherapeutic targets, such as glial clocks, clock-gated inflammatory mechanisms, and systemic comorbidities with circadian modulation, including diabetes and hypertension. Overall, the available evidence supports a close association between circadian disruption and both AD pathology and therapeutic response, while also highlighting important gaps in large-scale clinical trials. This time-oriented perspective may support the development of personalized, biomarker-guided, and rhythm-informed approaches to AD care. By bridging chronobiology and neurodegeneration, this review highlights how circadian precision medicine may refine future approaches to understanding and managing AD.},
}

@article {pmid42499414,
year = {2026},
author = {Mohammed, W and Al Ameri, M and Al Marzooqi, S and Alsafar, H and Olbrich, R and Mousa, M and Barayan, D and Magalhaes, T and Quilez, J and Reche, J and Alkaf, B and Shatila, A and Marzouka, NAD and Iqbal, I and Yousif, A and Rahma, A and Al Mannaie, A},
title = {Landscape of Apolipoprotein (APOE) in the Emirati Population and Recommendations for a Genotyping Approach for Amyloid-Beta Monoclonal Antibodies (Aβ-mAbs) in Alzheimer's Disease Patients.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e113196},
pmid = {42499414},
issn = {2168-8184},
abstract = {BACKGROUND: Apolipoprotein E (APOE) genotyping is increasingly recognized as a biomarker to support treatment decisions for Alzheimer's disease (AD) with the introduction of anti-amyloid monoclonal antibodies as promising therapeutic options. Although not yet incorporated into formal pharmacogenomic guidelines, regulatory authorities acknowledge its potential role in advancing precision medicine approaches.

METHODS: We reviewed AD cases diagnosed in 2024 from the Department of Health - Abu Dhabi records and assessed monoclonal antibody prescribing patterns. APOE genotypes were determined using the two defining variants, APOE rs429358 and rs7412, using whole-genome sequencing data from 506,734 participants enrolled in the Emirati Genome Program.

RESULTS: In 2024, 1,285 individuals were diagnosed with AD. Aducanumab was prescribed to eight patients between 2022 and 2024. In the Emirati Genome Program cohort, the allele frequencies of rs429358 and rs7412 were 8.3% and 4.2%, respectively. The most prevalent APOE genotype was ε3/ε3 (77.9%). The APOE ε4 risk allele was observed in 14.7% of participants, including 0.9% who were homozygous for ε4, while the protective APOE ε2 allele was present in 7.5%.

CONCLUSION: APOE profiling supports genotype-informed treatment strategies for anti-amyloid therapies. These findings establish a population-specific framework for integrating genetic information into the Emirati Genome Program pharmacogenomic report, enhancing precision medicine approaches for AD management in the UAE.},
}

@article {pmid42499619,
year = {2026},
author = {Li, PS and Liu, Y and Zhao, MR and Zhu, YQ and Shi, YX and Jing, MD and Hu, XW and Jiang, CH and Liu, XD and You, YL and Wu, CJ and Bie, NN and Liu, XM},
title = {Zizybeoside II From Jujube Fructus Prolongs Lifespan and Mitigates Alzheimer's Disease Progression in Caenorhabditis elegans Through HSF-1/HSP-16.2 Pathway.},
journal = {Food science & nutrition},
volume = {14},
number = {7},
pages = {e72151},
pmid = {42499619},
issn = {2048-7177},
abstract = {Jujube (Ziziphus jujuba Mill.) has been consumed as a nutraceutical and medicinal food in China for millennia. Recent studies have highlighted the nutritional and bioactive properties of jujube fruit extracts, with potential to mitigate Alzheimer's disease (AD) progression through longevity-enhancing effects. Our previous study explored the lifespan-extending mechanisms of Jujube Fructus extract (JE) in Caenorhabditis elegans (C. elegans). Here, we evaluated the efficacy of zizybeoside II (ZB), separated from JE through HPLC, in extending lifespan and ameliorating AD pathology in C. elegans. The results showed that ZB treatment significantly prolonged C. elegans lifespan while maintaining reproductive capacity, with concurrent enhancements in normal activity and stress resistance during aging. Additionally, we found that ZB effectively alleviated various β-Amyloid (Aβ)-induced neurotoxic phenotypes in AD worms, including paralysis and behavioral deficits. Mechanistic investigations in N2a/APP695 cells demonstrated that ZB reduced the accumulation of Aβ and phosphorylated tau (p-Tau) proteins, diminished oxidative stress levels through the HSF-1/HSP16.2 pathway, and thereby slowed the progression of AD. This study provides a theoretical basis for the subsequent clinical trials of ZB in delaying AD.},
}

@article {pmid42499998,
year = {2026},
author = {Ruesga Mundo, S},
title = {Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases.},
journal = {Frontiers in systems neuroscience},
volume = {20},
number = {},
pages = {1888548},
pmid = {42499998},
issn = {1662-5137},
abstract = {INTRODUCTION: Chronic neuroinflammation is a hallmark of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and neuropsychiatric disorders (major depression, schizophrenia). However, current models fail to explain why some individuals develop persistent neuroinflammation while others maintain homeostasis, nor why similar inflammatory pathology produces such diverse clinical phenotypes.

HYPOTHESIS: We propose that pathological neuroinflammation emerges from a failure of allostatic integrity-the capacity of the organism to maintain adaptive circular information flow across five interconnected levels: (1) genetic architecture and morphogenetic programming, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the psychoneuroimmuneendocrine (PINE) network, and (5) interoceptive-neuronal integration. When this circular flow is disrupted, maladaptive stable states become entrenched, perpetuating chronic inflammation.

DEVELOPMENT OF THE HYPOTHESIS: Synthesizing evidence from longitudinal and mechanistic studies (with foundational older works cited where necessary), we discuss how: (a) early-life stress epigenetically programs inflammatory reactivity; (b) elevated allostatic load predicts chronic neuroinflammation; (c) PINE network dysregulation perpetuates pro-inflammatory signaling; and (d) interoceptive dysfunction may prevent the downregulation of inflammation. Allostatic integrity is introduced as a dynamic systems-level property hypothesized to moderate the relationship between inflammatory pathology and clinical expression.

TESTABLE PREDICTIONS: The framework generates falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting transition to chronic neuroinflammation; (2) multidomain interventions targeting multiple levels will produce multiplicative (synergistic) effects; (3) patients with similar inflammatory profiles but contrasting allostatic integrity will show markedly different clinical trajectories; and (4) improvements in allostatic integrity will correlate with reduced neuroinflammation independent of direct anti-inflammatory therapies.

CONCLUSION: The Hierarchical-Circular Model reframes chronic neuroinflammation not as a linear cascade but as a potential systemic failure of biological memory and allostatic integrity. Pending empirical validation, this framework may offer a conceptual basis for biomarker development, multidomain prevention, and personalized treatment strategies.},
}

@article {pmid42502037,
year = {2026},
author = {Montano, CB and Chumki, SR and Wang, D and Palma, AM and Zhang, Z and Porsteinsson, AP},
title = {Brexpiprazole With Antidepressants for Agitation in Alzheimer's Dementia: Post Hoc Analysis.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.015},
pmid = {42502037},
issn = {1545-7214},
abstract = {OBJECTIVE: To analyze the efficacy and safety of brexpiprazole versus placebo on agitation symptoms in participants with Alzheimer's dementia, with and without concomitant antidepressants.

METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled trials of brexpiprazole (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified by antidepressant use. Efficacy was assessed using the Cohen-Mansfield Agitation Inventory (CMAI) and safety using treatment-emergent adverse events (TEAEs).

RESULTS: Brexpiprazole 2 or 3 mg/day improved CMAI Total score versus placebo in participants with concomitant antidepressant (n = 97; least squares mean difference at Week 12, -12.1 [95% confidence interval, -19.1 to -5.05]; t(77) = -3.4, p = 0.001; Cohen's d = 0.72) and without concomitant antidepressant (n = 513; -2.93 [-5.49 to -0.37]; t(487) = -2.2, p = 0.025; Cohen's d = 0.20). Falls were the only TEAE reported for ≥5% of participants with concomitant antidepressant (brexpiprazole, 6.5%; placebo, 5.7%).

CONCLUSION: In this exploratory post hoc analysis, brexpiprazole improved agitation symptoms and was generally well tolerated in participants with Alzheimer's dementia with and without concomitant antidepressants.},
}

@article {pmid42502360,
year = {2026},
author = {Houmani, A and Parul, FNU and Saeed, M and Skowronek, R and Katkoori, V and Pikuleva, IA and Grant, MB and Busik, JV and Yavari, M and Abela, GS},
title = {Cholesterol crystal formation and embolism in the central nervous system and their potential role in Alzheimer's disease.},
journal = {American heart journal plus : cardiology research and practice},
volume = {69},
number = {},
pages = {100826},
pmid = {42502360},
issn = {2666-6022},
abstract = {The brain and nervous tissues are very rich in cholesterol with local sterol biosynthesis being the primary source. The production of cholesterol in the brain may also lead to cholesterol crystal formation that in turn can cause inflammation which potentially can contribute to Alzheimer's disease. In this review we provide examples of cholesterol crystals (CCs) in human brains of Alzheimer patients. Moreover, cholesterol in the arterial circulation is also a major contributor to brain pathology. Specifically, CCs embolization released during plaque rupture may lead to reduced cognitive function, transient ischemic attacks, and ischemic strokes. Ischemic strokes can be caused by either thrombotic emboli from atrial fibrillation or CC emboli and platelets from ruptured plaques in the carotid arteries and aortic arch. CC emboli can cause blood flow obstruction, localized inflammation, and vasospasm of the local arterial vasculature, all contributing to ischemia and brain injury. Prevention and treatment of CC emboli with statins and aspirin has been found to be effective. Moreover, previous studies have demonstrated that both statins and aspirin can dissolve CCs. Thus, preventing formation and/or dissolving CCs could potentially be effective in reducing end organ injury induced by both CCs formation and emboli. Although further investigation with human studies remain lacking, recent studies have demonstrated prevention of thrombus formation induced by CCs may also provide another approach to inhibiting end-organ ischemic injury.},
}

@article {pmid42502675,
year = {2026},
author = {Yu, L and Alhoqail, WA and Mickymaray, S and Li, F},
title = {Cnicin Attenuates Aluminium Chloride-Induced Neurodegeneration Through Antioxidant and Anti-Inflammatory Mechanisms.},
journal = {Dose-response : a publication of International Hormesis Society},
volume = {24},
number = {3},
pages = {15593258261471150},
pmid = {42502675},
issn = {1559-3258},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. Aluminium chloride (AlCl3)-induced neurotoxicity mimics key pathological features of AD, including oxidative stress, neuroinflammation, and cholinergic dysfunction.

OBJECTIVE: This study aimed to evaluate the neuroprotective effect of cnicin in an AlCl3-induced rat model of Alzheimer-like neurodegeneration.

METHODS: Rats were divided into five groups: normal control, AlCl3 control (75 mg/kg/day, p.o.), AlCl3 with cnicin (20 and 40 mg/kg/day, p.o.), and AlCl3 with donepezil (5 mg/kg/day, p.o.) for 30 days. Behavioral performance was assessed using hanging wire and beam walking tests. Biochemical parameters, including acetylcholinesterase (AChE), antioxidant enzymes (SOD, CAT, GSH), malondialdehyde (MDA), and inflammatory cytokines (TNF-α, IL-1β) were analyzed, along with histopathology.

RESULTS: AlCl3 administration induced significant behavioral deficits, increased AChE activity, oxidative stress, neuroinflammation, and neuronal damage. Cnicin treatment dose-dependently improved motor function, reduced AChE activity, restored antioxidant levels, decreased lipid peroxidation, and suppressed inflammatory markers. Histological analysis confirmed preservation of neuronal architecture, comparable to that of donepezil.

CONCLUSION: Cnicin exhibits significant neuroprotective effects against AlCl3-induced neurodegeneration by modulating cholinergic activity, oxidative stress, and inflammation, suggesting its potential as a therapeutic agent for AD.},
}

@article {pmid42503498,
year = {2026},
author = {Lee, YS and Roh, S and Han, J and Moon, I and Stone, ST and Warne, DK},
title = {Alzheimer's Disease Knowledge Among American Indians: The Role of Social Determinants of Health.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261471592},
doi = {10.1177/14713012261471592},
pmid = {42503498},
issn = {1741-2684},
abstract = {American Indian populations experience a disproportionately high prevalence of risk factors for Alzheimer's disease and related dementias. This study assessed Alzheimer's disease knowledge across seven domains and identified factors associated with overall and domain-specific Alzheimer's disease knowledge among American Indian adults. Guided by the social determinants of health framework, we conducted a cross-sectional survey of American Indian adults residing in South Dakota. A total of 227 participants completed a self-administered survey questionnaire measuring Alzheimer's disease knowledge across seven domains. Multivariable regression analyses were performed to examine factors associated with overall Alzheimer's disease knowledge and each domain. Participants demonstrated 63.5% accuracy in overall Alzheimer's disease knowledge (M = 18.7, SD = 4.1), indicating a moderate level of knowledge. Knowledge varied across domains: participants were most knowledgeable about the life impact of Alzheimer's disease and least knowledgeable about risk factors and symptoms. Four domains were found to be statistically significant: disease course, treatment and management, risk factors, and caregiving. Higher educational attainment and employment status were significantly associated with greater overall Alzheimer's disease knowledge. Education was the most consistent factor associated with greater knowledge across all four domains, whereas other social determinants of health variables (e.g., social support from significant others, lower depressive symptoms, health status, exercise) showed domain-specific associations. Findings highlight the need for educational outreach and culturally tailored interventions grounded in the social determinants of health and responsive to American Indian community contexts. Notable gaps in knowledge-particularly regarding risk factors and symptoms-suggest priority areas for Alzheimer's disease prevention efforts. Health initiatives should address key social determinants, including education, employment, social support, health/mental health status, and health behaviors. Interventions must be developed in partnership with Indigenous leaders and health professionals to ensure culturally relevant, community-driven, and holistic approaches that improve Alzheimer's disease knowledge and support Alzheimer's disease prevention in American Indians.},
}

@article {pmid42504206,
year = {2026},
author = {Zhang, Y and Qin, G and Lian, Q and Sun, Y and Liu, Z and Chen, B and Li, Z and Li, N and Song, R and Wang, Y},
title = {Deciphering the Multi-Target Therapeutic Mechanisms of Traditional Chinese Medicine Against Alzheimer's Disease: A Network Pharmacology Perspective.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {597886},
pmid = {42504206},
issn = {1177-8881},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Medicine, Chinese Traditional ; *Network Pharmacology ; *Drugs, Chinese Herbal/therapeutic use/pharmacology/chemistry ; Signal Transduction/drug effects ; Animals ; },
abstract = {Alzheimer's disease (AD) poses a growing threat to global health, with no disease-modifying therapies currently available to cure or reverse its progression. Given its favorable safety profile and multi-target nature, Traditional Chinese Medicine (TCM) has attracted increasing attention as a potential strategy for AD prevention and treatment. In recent years, network pharmacology (NP) has emerged as a valuable predictive and analytical tool in TCM research, offering insights into the potential mechanisms underlying AD interventions. This review aims to systematically outline the methodology and commonly used databases in TCM NP, summarize the main TCM monomers and compounds studied for AD over the past decade, and identify five core signaling pathways, namely, the PI3K/Akt signaling pathway, the MAPK signaling pathway, the JAK-STAT signaling pathway, the AGE-RAGE signaling pathway, and the Nrf2 signaling pathway, implicated in pathogenesis and TCM action. To guide further exploration of TCM's role in AD management and to support subsequent research on its disease mechanisms and therapeutic strategies.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Medicine, Chinese Traditional
*Network Pharmacology
*Drugs, Chinese Herbal/therapeutic use/pharmacology/chemistry
Signal Transduction/drug effects
Animals

@article {pmid42504849,
year = {2026},
author = {Kumar, S and Burhan, AM and Colman, S and Chu, L and Davies, S and Derkach, P and Elmi, S and Gerretsen, P and Graff-Guerrero, A and Greenway, K and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Ma, C and Moghabghab, R and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Schoer, N and Streiner, DL and Van Bussel, L and Rajji, TK and , },
title = {Standardizing care for agitation in Alzheimer's disease, results from a randomized controlled trial of an integrated care pathway versus usual care - the StaN trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71610},
doi = {10.1002/alz.71610},
pmid = {42504849},
issn = {1552-5279},
support = {//Centre for Aging and Brain Health Innovation/ ; //Brain Canada Foundation through the Canada Brain Research Fund/ ; },
mesh = {Humans ; Female ; Male ; Double-Blind Method ; *Psychomotor Agitation/therapy/drug therapy/etiology ; *Alzheimer Disease/complications/therapy/drug therapy ; Aged ; Aged, 80 and over ; Polypharmacy ; Canada ; Treatment Outcome ; Long-Term Care ; Psychotropic Drugs/therapeutic use ; },
abstract = {BACKGROUND: Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed and evaluated an Integrated Care Pathway (ICP) for the management of agitation in dementia.

METHODS: This was a double-blind randomized controlled trial at 12 inpatient units and long-term-care homes (LTCHs) across Canada. Participants were randomized 1:1 to the ICP or treatment-as-usual (TAU). Primary outcomes were Cohen Mansfield Agitation Inventory (CMAI) and psychotropic polypharmacy at 12 weeks.

RESULTS: We randomized 185 participants (93 inpatients, 92 in LTCHs). For CMAI, there were no significant time-by-treatment-group interactions among inpatients (F4, 299.3 = 1.7, p = 0.14) or LTCH residents (F4, 296.0 = 0.87, p = 0.48). For polypharmacy, there were significant time-by-treatmentgroup interactions among both inpatients (χ 7 2 = 15.3, p = 0.032) and LTCH residents (χ 7 2 = 30.0, p < 0.001), with lower rates of polypharmacy in the ICP group at certain time points, but not at week 12.

CONCLUSIONS: Standardizing care for agitation in dementia may result in lesser polypharmacy without affecting efficacy. Future studies should assess the ICP in the broader community and outpatients.},
}

Humans
Female
Male
Double-Blind Method
*Psychomotor Agitation/therapy/drug therapy/etiology
*Alzheimer Disease/complications/therapy/drug therapy
Aged
Aged, 80 and over
Polypharmacy
Canada
Treatment Outcome
Long-Term Care
Psychotropic Drugs/therapeutic use

@article {pmid42505964,
year = {2026},
author = {Galizzi, G},
title = {Omega-3 Fatty Acids and Alzheimer's Disease: Toward a New Understanding of Neuroprotective Mechanisms and Intervention Strategies.},
journal = {Marine drugs},
volume = {24},
number = {7},
pages = {},
doi = {10.3390/md24070224},
pmid = {42505964},
issn = {1660-3397},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Docosahexaenoic Acids/pharmacology ; Dietary Supplements ; Brain/drug effects/metabolism ; Eicosapentaenoic Acid/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Despite recent advances, current therapies offer little benefit, and AD remains a significant challenge. Polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have attracted attention for their neuroprotective effects primarily through anti-inflammatory and antioxidant properties, but also for their ability to influence membrane fluidity and neuronal function. DHA is the predominant omega-3 PUFA in nerve cell membranes and is critical for synaptic plasticity and cognitive function. Some evidence has demonstrated that marine omega-3 supplementation reduces Aβ deposition, modulates microglial activation, and prevents cognitive decline in animal models. Even with heterogeneous results, preclinical and clinical studies suggest that long-term DHA/EPA supplementation can improve cognitive function in subjects with mild cognitive impairment (MCI) and reduce neuroinflammation markers. However, individual variability and brain bioavailability pose significant challenges. This review summarizes and discusses the current knowledge on the importance of PUFAs for human health, exploring novel mechanistic hypotheses, such as the effect of omega-3 fatty acids on brain iron homeostasis, the microbiota-gut-brain axis, the glymphatic system, and miRNAs. Furthermore, it focuses on the therapeutic potential of PUFAs in the treatment of AD and proposes future directions for translational research.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
*Fatty Acids, Omega-3/pharmacology/therapeutic use
Docosahexaenoic Acids/pharmacology
Dietary Supplements
Brain/drug effects/metabolism
Eicosapentaenoic Acid/pharmacology

@article {pmid42497640,
year = {2026},
author = {Malcangio, M and Sideris-Lampretsas, G},
title = {Chronic pain in Alzheimer disease and the role of neuroimmune interactions.},
journal = {Pharmacological reviews},
volume = {78},
number = {5},
pages = {100149},
doi = {10.1016/j.pharmr.2026.100149},
pmid = {42497640},
issn = {1521-0081},
abstract = {Chronic pain conditions affect a large proportion of the global population and pain has tremendous personal and economic impact, affecting quality of life and ability to work while imposing a significant burden on families and health care systems. Neurological disorders and painful conditions are frequently accompanied by chronic pain, which is often jointly diagnosed with age-related neurodegenerative diseases, however, many patients do not receive adequate treatment. This review aims to create a working framework around the issue of under-recognized/undertreated chronic pain in Alzheimer disease by offering an in-depth overview of the mechanisms driving chronic pain and how we can leverage this knowledge to advance therapeutics approaches for these patients with an emphasis on the immune system. SIGNIFICANCE STATEMENT: Chronic pain conditions are prevalent among the aging population, and they positively associate with dementia. The incidence of chronic pain is associated with neuropsychiatric symptoms of dementia and pain management should aim for effective treatments regardless of cognitive status.},
}

@article {pmid42497811,
year = {2026},
author = {Tağraf, B and Kaygusuz, D and Yerlikaya, D and Oğul, ÖE and Hanoğlu, L},
title = {The effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting on early-to-mid-stage Alzheimer's disease: a randomised controlled trial.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {9},
pages = {100930},
doi = {10.1016/j.jnha.2026.100930},
pmid = {42497811},
issn = {1760-4788},
abstract = {INTRODUCTION: This study evaluates the effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting as an individualized adjunct to standard treatment on cognitive function in early/mid-stage Alzheimer's patients.

METHODS: This assessor-blinded, randomized controlled trial enrolled 60 Alzheimer's disease (AD) patients (CDR 1-2; aged 55-85), randomized to intervention (n = 30; intervention + standard care) or control (n = 30; standard care). Cognition and brain structure were assessed at baseline and 6 months. Individual cognitive changes were analyzed using Reliable Change Index (RCI).

RESULTS: Cognitive change scores differed significantly between groups (p < 0.001). The mean Mini Mental State Examination (MMSE) score increased by +0.9 in the intervention group, while a decrease of -1.5 points was observed in the control group. RCI analysis indicated stability in 93% of intervention and 70% of control participants, with cognitive improvement in 7% and 3.3%, respectively.

DISCUSSION: The intervention method has the potential to stabilize cognitive decline in AD and promote improvement at the individual level. The response to the intervention is closely related to the individual's metabolic phenotype and structural brain integrity.

ETHICAL APPROVAL: Istanbul Medipol University Non-Interventional Clinical Research Ethics Committee on March 6, 2025, under number 242 and the study was carried out in accordance with the Declaration of Helsinki and its later amendments.

CLINICALTRIALS: gov ID: NCT06898424.},
}

@article {pmid42498669,
year = {2026},
author = {McDiarmid, A},
title = {Sustaining Drug Discovery Amid the Limits of Alzheimer's Disease Immunotherapies.},
journal = {eNeuro},
volume = {13},
number = {7},
pages = {},
doi = {10.1523/ENEURO.0112-26.2026},
pmid = {42498669},
issn = {2373-2822},
mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; *Immunotherapy/methods ; *Drug Discovery ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Accumulation of insoluble extracellular amyloid-β (Aβ) plaques and intraneuronal fibrillary hyperphosphorylated tau fibrils in the brain are widely believed to contribute to the progressive neurodegeneration and neuronal loss characteristic of the Alzheimer's disease and the associated dementia. Anti-amyloid immunotherapies that reduce cerebral Aβ burden in affected individuals have been approved based on biological outcomes from clinical trials. However, the extent to which Aβ clearance translates into improved meaningful clinical, cognitive, and functional benefit versus risk and cost is unclear based on available data. Here, the critical barriers that limit the impact of anti-amyloid immunotherapies, including aducanumab, lecanemab, and donanemab, are discussed. Treatment slows cognitive decline by ∼20-30% in certain patient subsets, but absolute improvements in cognitive and functional outcomes remain modest. Independent analyses of how treatment impacts health span suggests statistically significant trial results may not translate into significant real-world benefit. Response is most significant in cases of early-stage disease where levels of copathology tau are low. Edema and brain hemorrhage occur frequently, particularly in carriers of APOE-e4 alleles, an established genetic risk factor for Alzheimer's disease, raising safety concerns which led to some regulators banning treatment in this patient group. Strict clinical trial eligibility criteria, high treatment costs relative to patient benefit, intensive during-treatment monitoring, and the absence of population-level screening programs further limit treatment accessibility and generalizability. Emerging evidence of accelerated brain atrophy and immunotherapy tolerance further complicates benefit-risk consultation. Sustaining drug- discovery pipelines by exploring combination therapies, tau-targeted approaches, drug repositioning, and novel small molecules through will be essential to provide comprehensive treatment options and personalized treatment plans for affected patients.},
}

Humans
*Alzheimer Disease/therapy/immunology/drug therapy
*Immunotherapy/methods
*Drug Discovery
Animals
Amyloid beta-Peptides/metabolism

@article {pmid42493137,
year = {2026},
author = {Cardoso, E and Serra, AC and Coelho, JFJ and Pereira, P},
title = {Glycopolymers as emerging modulators of Amyloid-β aggregation: structure-activity relationships and therapeutic potential.},
journal = {Carbohydrate polymers},
volume = {388},
number = {},
pages = {125572},
doi = {10.1016/j.carbpol.2026.125572},
pmid = {42493137},
issn = {1879-1344},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Structure-Activity Relationship ; Animals ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Despite ongoing debate about the "amyloid hypothesis", the imbalance between the production and clearance of β-amyloid (Aβ) peptides in the brain remains one of the most compelling explanations for the progression of Alzheimer's disease. Current strategies therefore focus on discovering clinically relevant therapeutic agents that target Aβ peptides and amyloid structures. Because of their unique and attractive properties - biocompatibility, non-immunogenicity, non-toxicity, and ease of functionalization and production - the use of glycopolymers as amyloid inhibitors has generated interest in therapeutic research for Alzheimer's disease. This review provides a comprehensive and critical overview of the literature on glycopolymers in the treatment of Alzheimer's disease. It begins with a description of the disease's neuropathological mechanisms and the formulations approved by the FDA or currently in clinical trials. The second part discusses the use of glycopolymers as amyloid inhibitors, which prevent the formation of neurotoxic soluble oligomers and subsequent plaques observed in Alzheimer's disease. This is achieved by binding to monomers, blocking self-aggregation, and interrupting toxic interactions, offering a therapeutic strategy to halt disease progression. Finally, the main conclusions and perspectives on the use of glycopolymers as amyloid inhibitors are presented.},
}

Humans
*Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism/pathology
Structure-Activity Relationship
Animals
Protein Aggregates/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid42494775,
year = {2026},
author = {Lavigne, SB and Hromas, G and LaRoche, A and Parker, AS and Abdullah, MS and Fernandez, RA and Wang, CP and de Erausquin, G and Salardini, A and Tanner, J and Kautz, TF and Castro, J and Mendoza, C and Seshadri, S and Sullivan, AC},
title = {Frontotemporal dementia in Hispanic populations: Regional and national comparisons.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70396},
pmid = {42494775},
issn = {2352-8729},
abstract = {INTRODUCTION: Although Hispanic/Latine populations experience higher dementia rates, they remain underrepresented in frontotemporal dementia (FTD) research. This study examines clinical manifestations of FTD within a South Texas Hispanic/Latine cohort compared to national data.

METHODS: Participants diagnosed with FTD were included from (1) our FTD clinic, the South Texas Alzheimer's Disease Research Center, and local Advancing Research and Treatment in Frontotemporal Lobar Degeneration-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Longitudinal Frontotemporal Lobar Degeneration cohort (Hispanic: n = 17; White non-Hispanic: n = 22), and (2) the National Alzheimer's Coordinating Center dataset (Hispanic: n = 24; White non-Hispanic: n = 407; National Institute on Aging/National Institutes of Health Grant U24 AG072122). Clinical, neuroimaging, and neuropsychological data were harmonized for cross-cohort comparisons.

RESULTS: Hispanic participants presented with more movement-related symptoms and advanced cognitive impairment at diagnosis than non-Hispanic Whites. Diagnostic delays averaged 4 years from symptom onset. Educational disparities significantly contributed to health-care access differences.

DISCUSSION: Findings underscore diagnostic severity and systemic barriers faced by Hispanic populations with FTD, emphasizing the need for culturally sensitive diagnostic tools and interventions for equitable dementia care.},
}

@article {pmid42495050,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining eligibility assessment for Alzheimer's disease-modifying therapies: Prediction of MMSE scores using the digital clock and recall.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1799372},
pmid = {42495050},
issn = {2673-253X},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks of perpetuating health disparities, given the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR™)-a rapid, FDA-listed digital cognitive assessment-to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 (BH) study (NCT04733989, N = 945). Participants were clinically classified as cognitively unimpaired, mild cognitive impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model on 70% of the sample, using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was validated using the remaining 30% of Bio-Hermes-001 and an independent external validation cohort from the Apheleia study (NCT05364307, N = 238).

RESULTS: The machine learning model predicted MMSE scores with a root-mean-squared error (RMSE) of 2.43 in the BH test set. This error margin falls within the established test-retest reliability range of the manual MMSE itself (∼4.0-4.2 points at short inter-test intervals), providing evidence that the predicted score is of comparable precision to a repeat human administration of the MMSE. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). In the BH held-out test set, the model showed comparable performance across Race (White RMSE = 2.46; Non-White RMSE = 2.25) and Ethnicity (Hispanic RMSE = 2.19; Non-Hispanic RMSE = 2.45), a balanced pattern also observed in the Apheleia-001 external cohort. Exploratory demographic analyses on prediction errors, including Age, Sex, Race, and Ethnicity, yielded significant differences only for Sex and Age in Apheleia, with signed errors becoming progressively more negative (i.e., increasing under-prediction) at older ages for the latter. This scarcity of statistical differences across cohorts suggested that our predictions were fair.

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}

@article {pmid42495562,
year = {2026},
author = {Pujar, KG and Purohit, D and Shetty, RP and S, P and Kolachi, KY and Bharathi H M, A and Achar, PG and P, P},
title = {Pharmacophore-driven design and biological evaluation of heterocyclic PDE4B inhibitors for Alzheimer's disease.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42495562},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition marked by a gradual loss of cognitive function, impaired synaptic signalling, and sustained neuroinflammatory responses. Among the molecular pathways associated with disease progression, cyclic adenosine monophosphate (cAMP) signalling, plays a crucial factor in disruption of cellular homeostasis. Phosphodiesterase-4 (PDE4), especially the PDE4B isoform, controls intracellular cAMP levels in neuronal and glial cells, which affects inflammatory signalling and synaptic plasticity in the brain. Therefore, selectively targeting PDE4B is a novel approach to identify the small molecule's therapeutic activity to restore the cAMP signalling, with parallel regulation of the dose-limiting side effects. GSK356278 and Rolipram are the known PDE4B modulators, which have been considered for the current study to generate significant pharmacophoric features and execute drug design as CNS-active PDE4B inhibitors. Six heterocyclic derivatives were designed and synthesised by altering the core scaffold in order to maximise hydrophobicity, CNS permeability, and Q-pocket engagement without depending on direct Zn[2+] or Mg[2+] coordination. Among these, molecule VCHH-19 and VCPH-19 demonstrated significant CNS compatibility and good binding stability. PC12 cell lines were chosen to verify the in vitro neuroprotective response, and the Drosophila model for in vivo for AD assessment. All of these results indicated the significance of pyridine-based heterocycles molecules as potential candidates for PDE4B-targeted AD treatment.},
}

@article {pmid42496756,
year = {2026},
author = {Sahu, SK and Nayak, M and Samal, A and Jena, S and Pradhan, J and Dandapat, J and Samanta, L and Jena, S},
title = {T3 and curcumin regulates collagen-IV and collagen-VI expression: role in suppression of amyloid-β via TGFβ1-Sp1 signaling in hypothyroid mice brain.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42496756},
issn = {1573-7365},
support = {26913/HED/HE-PTC-WB-02-17//OHEPEE and S&T Department, Government of Odisha/ ; 584/83/OSHEC//OURIIP, OSHEC, Government of Odisha/ ; },
mesh = {Animals ; *Curcumin/pharmacology/therapeutic use ; *Hypothyroidism/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Triiodothyronine/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Mice ; *Transforming Growth Factor beta1/metabolism ; *Collagen Type IV/metabolism/biosynthesis ; Male ; *Brain/metabolism/drug effects ; Mice, Inbred BALB C ; Sp1 Transcription Factor/metabolism ; },
abstract = {Hypothyroidism has been associated with cognitive disorders and high risk of neurodegenerative disorders like Alzheimer's disease (AD), which is caused by amyloid-β (Aβ) accumulation in brain. The aim of the study is to examine the therapeutic ability of triiodothyronine (T3) and curcumin in regulating two key extracellular matrix proteins (ECM), collagen IV and collagen VI in brain since both drugs have neuroprotective and anti-fibrotic effects. The study further explored the possible role of signaling molecules such as transforming growth factor β1 (TGFβ1) and specificity protein 1 (Sp1) in regulating the effects of T3 and curcumin on Aβ accumulation and ECM protein expression. Experiment was carried on Balb/c mouse model by inducing hypothyroidism with 0.05% PTU followed by treatment of T3, curcumin and a combination of both. The study revealed a significant increase in the expression of collagen IV and VI, along with elevated levels of TGFβ1 and Sp1 signalling proteins, in hypothyroid conditions in response to increased Aβ expression in both the cortex and hippocampus. Western blot and RT-PCR analysis showed that T3 and curcumin treatment downregulate the levels of ECM proteins, the APP gene, Aβ protein, and the signaling factors. The study found that T3 and curcumin treatment downregulates the collagen IV and VI expression by negatively regulating TGFβ1 and Sp1 when expression of APP and Aβ are low. T3 and coadministration of T3 with curcumin more effectively regulate thyroid function and ECM protein expression in both the cortex and hippocampus. Whereas curcumin alone exhibits limited impacts under the experimental conditions in our study, this may due to bioavailability, dosage or treatment duration which need to further investigation. Our results indicate a novel therapeutic approach for understanding Aβ pathology associated with hypothyroidism, emphasizing the potential association between thyroid hormone and nature-based compounds, such as curcumin, in modulating ECM dynamics and neuroprotection.},
}

Animals
*Curcumin/pharmacology/therapeutic use
*Hypothyroidism/metabolism/drug therapy
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Triiodothyronine/pharmacology/therapeutic use
Signal Transduction/drug effects
Mice
*Transforming Growth Factor beta1/metabolism
*Collagen Type IV/metabolism/biosynthesis
Male
*Brain/metabolism/drug effects
Mice, Inbred BALB C
Sp1 Transcription Factor/metabolism

@article {pmid42489438,
year = {2026},
author = {Saadawy, M and Majeed, M and Saadawy, E and , },
title = {APOE4-specific glymphatic effects on clinical progression in the Alzheimer's Disease Neuroimaging Initiative with pathological correlates in the A4 study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469565},
doi = {10.1177/13872877261469565},
pmid = {42489438},
issn = {1875-8908},
abstract = {BackgroundThe APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, some carriers show "clinical resilience", maintaining their cognition despite high risk.ObjectiveWe hypothesized that the glymphatic system, the brain's waste clearance pathway, may attenuate APOE ε4-mediated neurodegeneration, and tested this in two independent cohorts.MethodsWe analyzed 625 cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) discovery cohort and 447 amyloid-positive participants from the preclinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) validation cohort. Glymphatic function was estimated using the analysis of diffusional kurtosis imaging along the perivascular space (DTI-ALPS) index in ADNI and choroid plexus (CP) [18]F-Flortaucipir PET uptake in the A4 study. Primary outcomes were clinical conversion to dementia (ADNI) and hippocampal tau pathology (A4).ResultsIn the discovery cohort, we observed a trend toward ALPS × APOE4 interaction (p = 0.057, not reaching conventional statistical significance). Carriers with preserved function (high ALPS) showed a reduced conversion risk (hazard ratio = 0.52, 95% CI: 0.27-0.99) compared to those with low function. In the validation cohort, glymphatic interface dysfunction (higher CP tau) strongly predicted hippocampal tau burden (p < 0.0001). However, the gene-specific interaction was not replicated (p = 0.928); clearance failure predicted pathology regardless of genotype. Exploratory fluid biomarker analyses in ADNI did not reveal significant interactions.ConclusionsThese findings suggest that preserved glymphatic function is associated with clinical resilience in APOE ε4 carriers, though the interaction was borderline (p = 0.057) and should be considered hypothesis-generating. The strong pathological associations with clearance integrity highlight a biologically plausible mechanism in AD pathogenesis that warrants further investigation.},
}

@article {pmid42489531,
year = {2026},
author = {Farzeen, I and Nazir, MM and Jaan, Z and Ghaffar, W and Masood, A and Yasmeen, M and Ashraf, A and Różański, H},
title = {Biochemical modulators of synaptic plasticity: New horizons in Alzheimer's disease treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469864},
doi = {10.1177/13872877261469864},
pmid = {42489531},
issn = {1875-8908},
abstract = {Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.},
}

@article {pmid42489536,
year = {2026},
author = {Costa, T and Sensi, SL and Høilund-Carlsen, PF and Robakis, NK and Vissel, B and Espay, AJ},
title = {Do anti-amyloid therapies demonstrate clinically meaningful benefit? A Bayesian reappraisal.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469870},
doi = {10.1177/13872877261469870},
pmid = {42489536},
issn = {1875-8908},
abstract = {BackgroundRecent anti-amyloid trials have been interpreted as evidence of clinical benefit in Alzheimer's disease, although their relevance remains debated.ObjectiveTo reinterpret pooled randomized evidence on anti-amyloid therapies within a Bayesian framework focused on benefit and harm.MethodsPooled estimates from a recent Cochrane review were reanalyzed using posterior probability estimation with clinically relevant thresholds.ResultsThe probability that treatment effects reached clinically meaningful thresholds was generally low, whereas the probability of substantial harm, particularly amyloid-related imaging abnormalities, was high.ConclusionsCurrent randomized evidence suggests that statistically significant anti-amyloid effects may not translate into clinically meaningful benefit.},
}

@article {pmid42489967,
year = {2026},
author = {Søraas, A and Engvig, A and Alnæs, D and Karim, LN and Danilova, E and Istre, MS and Nygaard, S and Utgård, TR and Ceprnjic, S and Reiakvam, O and Edvardsen, E and Westlye, LT and Nygaard, AB and Dahl, JA and Nissen-Meyer, LSH and Ihle-Hansen, H and Holland, P},
title = {Interstitial fluid rejuvenation through young-donor plasma exchange in cognitively impaired patients: a pilot safety and feasibility study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42489967},
issn = {2509-2723},
abstract = {Heterochronic parabiosis improves physiological and cognitive function in aging rodents; these benefits appear to be derived from the removal of aged blood plasma components and the addition of younger ones. In humans, removing plasma from older individuals with Alzheimer's disease (AD) and replacing it with saline and albumin delayed cognitive deterioration in a large clinical trial. However, mimicking heterochronic parabiosis in humans by removing large volumes of a patient's blood plasma and replacing it with plasma from young and healthy donors has not been tested. Here, we have performed a pilot study to characterize the feasibility and safety of such a procedure, replacing between 16 and 26 L of patient blood plasma with young (ages 18-24) donor blood plasma for twelve patients who recently received a diagnosis of mild cognitive impairment with biomarker evidence of AD. The dose and time interval between plasma exchanges was tailored to maximize equilibration of donor plasma components into the interstitial fluid, with the aim of achieving what we term interstitial rejuvenation. We explored three permutations of a plasma exchange protocol with different treatment intensities and doses, each performed on three to five patients. We present data on safety, feasibility, patient burden, resource use of the treatments, preliminary measurements of clinical variables, and short-term cognitive trajectories in the patients. The procedures were feasible, and the adverse events observed were consistent with known risks of plasma exchange, supporting further investigation of treatment efficacy in a larger controlled trial. This safety and feasibility study was first registered 22 December 2023 at ClinicalTrials.gov and given the identifier NCT06234436.},
}

@article {pmid42490036,
year = {2026},
author = {Just, C and Seibert, K and Chan, C and Maldonado-Correa, C and Jones, D},
title = {Considerations in Alzheimer's Disease in Women.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42490036},
issn = {1534-6293},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; Female ; *Sex Characteristics ; Biomarkers ; tau Proteins/metabolism ; },
abstract = {PURPOSE OF REVIEW: To examine sex differences in Alzheimer's disease and cognition with a focus on hormonal transitions, biomarker trajectory, and implications for diagnosis and treatment.

RECENT FINDINGS: Women account for nearly two-thirds of individuals with Alzheimer's disease and demonstrate important biological and clinical differences compared with men. APOE ε4 confers greater risk in women, while menopause, depression, chronic stress, adverse pregnancy outcomes, and metabolic dysfunction may further increase vulnerability. Biomarker studies suggest that amyloid trajectories are broadly similar between sexes, but women exhibit earlier or greater tau accumulation once amyloid pathology is present. Women may maintain verbal memory performance longer than men despite underlying pathology, potentially delaying diagnosis. Emerging plasma biomarkers, particularly p-tau217, may improve early detection, monitoring, and treatment. Alzheimer's disease in women reflects a complex interaction between sex-specific biology, hormonal transitions, psychosocial factors, and neurodegenerative processes. Recognizing these differences has important implications for cognitive assessment, biomarker interpretation, diagnosis, and application of disease-modifying therapies.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
Female
*Sex Characteristics
Biomarkers
tau Proteins/metabolism

@article {pmid42490707,
year = {2026},
author = {Cossette-Lefebvre, M and Bergeron, N},
title = {[Cooccurrence of catatonia, delirium and dementia in an elderly woman: A case report].},
journal = {Sante mentale au Quebec},
volume = {51},
number = {1},
pages = {95-104},
pmid = {42490707},
issn = {1708-3923},
mesh = {Humans ; Female ; *Catatonia/complications/diagnosis ; *Dementia/complications/diagnosis ; *Delirium/complications/diagnosis ; Aged ; },
abstract = {Catatonia is a severe but underrecognized neuropsychiatric syndrome that is frequently misdiagnosed as delirium or dementia in older adults, resulting in delayed and potentially inappropriate treatment. A 79-year-old woman was admitted for rapid cognitive decline, significant weight loss, and social withdrawal. Initial evaluations suggested major depressive disorder or dementia. Neurological investigations were inconclusive. Following the initiation of psychotropic medication, psychiatric assessment revealed mutism, posturing, and marked psychomotor retardation, fulfilling DSM-5 criteria for catatonia. A lorazepam challenge test confirmed the diagnosis. Psychotropic medications were discontinued, and lorazepam was titrated to 2 mg 4 times daily, resulting in significant clinical improvement. Subsequent brain positron emission tomography (PET) imaging along with clinical evidence supported the presence of an underlying Alzheimer's disease. However, the emergence of superimposed delirium required gradual benzodiazepine tapering. Memantine was subsequently introduced, allowing lorazepam withdrawal and full symptomatic remission. The patient was discharged home. During outpatient follow-up, recurrence of partial symptoms prompted consideration of alternative therapeutic strategies. This case underscores the importance of recognizing catatonia in older adults presenting with cognitive impairment. It highlights the diagnostic and therapeutic challenges posed by the coexistence of catatonia, delirium, and neurodegenerative disease, and emphasizes the need for early identification and a multidisciplinary approach to optimize outcomes.},
}

Humans
Female
*Catatonia/complications/diagnosis
*Dementia/complications/diagnosis
*Delirium/complications/diagnosis
Aged

@article {pmid42490986,
year = {2026},
author = {Kim, GH and Yoon, HJ and Kim, EH and Kim, JY and Yeom, J and Kang, SY and Lee, B and Jeong, JH},
title = {Six-month real-world amyloid PET outcomes after lecanemab: Greater amyloid reduction at the MCI stage than in dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70300},
pmid = {42490986},
issn = {2352-8737},
abstract = {INTRODUCTION: Evidence from routine clinical practice regarding stage-dependent responses to lecanemab remains limited. We examined early amyloid positron emission tomography (PET) and clinical trajectories according to disease stage in a real-world cohort.

METHODS: Among 89 patients who received lecanemab, 50 individuals with baseline amyloid positivity and follow-up amyloid PET were included in the primary amyloid PET efficacy analysis. Amyloid burden was quantified using the Centiloid scale. Longitudinal Centiloid trajectories were analyzed using linear mixed-effects models including disease stage, time from baseline amyloid PET, and the disease stage × time interaction, with adjustment for cumulative dose exposure, age, sex, and apolipoprotein E (APOE) ε4 carrier status. Cognitive and functional outcomes were assessed using mixed-effects models.

RESULTS: Amyloid burden decreased substantially during follow-up. After adjustment for cumulative dose exposure, age, sex, and APOE ε4 carrier status, the disease stage × time interaction was significant (β = +1.62 Centiloid/month; 95% confidence interval, 0.80 to 2.43; p < 0.001), indicating a faster rate of Centiloid reduction in patients with mild cognitive impairment (MCI) than in those with dementia (estimated -2.34 vs. -0.72 Centiloid/month). Conversion to amyloid-negative status (full treatment-related amyloid clearance) occurred in 9 of 50 patients (18.0%) and was more frequent at the MCI stage (p = 0.022). Patients treated at the MCI stage also showed more favorable short-term cognitive and functional trajectories than those treated at the dementia stage.

DISCUSSION: In real-world clinical practice, lecanemab treatment was associated with substantial amyloid reduction, with faster amyloid clearance observed at the MCI stage. These findings support the potential value of earlier intervention with anti-amyloid therapy, although longer follow-up and controlled comparisons are needed to determine whether early biomarker changes translate into sustained clinical benefit.},
}

@article {pmid42491022,
year = {2026},
author = {Yao, W and Lv, T and Zheng, W and Liu, Y and Shi, X and Zhang, Y and Song, Y and Bai, Y and Bai, F},
title = {Associations between neuronavigated rTMS-mediated functional connectome plasticity and neurotransmitter receptors in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70294},
pmid = {42491022},
issn = {2352-8737},
abstract = {INTRODUCTION: Cognitive improvement is mediated by repetitive transcranial magnetic stimulation (rTMS) in Alzheimer's disease (AD), and connectome gradient analysis has important potential to explore more comprehensive information for treatment efficacy. However, it remains unclear whether and how rTMS mediates connectome gradient reconstruction and its spatial neurotransmitter associations in subjects on the AD spectrum.

METHODS: A total of 84 subjects on the AD spectrum underwent 4 weeks of conventional neuronavigated rTMS targeting the left angular gyrus (20 Hz, 20 sessions over 4 weeks, 20 minutes per session), including 60 subjects with true stimulation and 24 with sham stimulation. This study identified functional connectome gradients and investigated their neuroplasticity between pre- and post-rTMS intervention. A support vector regression model was subsequently used to explore the cognitive prediction value of baseline measures. Finally, connectome‒neurotransmitter association analysis was used to investigate neurotransmitter profiles related to rTMS therapeutic efficacy.

RESULTS: These findings showed that rTMS treatment mainly mediated the decreased gradient values in the somatomotor regions and such baseline values of these regions showed preliminary predictive value for memory improvement after treatment (R [2]: 0.40-0.63, mean absolute error: 1.54-3.19, root mean square error: 1.98-3.94, p = 0.0002). Moreover, connectome-neurotransmitter association analysis suggested spatial associations between these gradient changes and normative metabotropic glutamate receptor 5 (mGluR5) and 5-hydroxytryptamine receptor 2A (5HT2a) receptor distributions.

DISCUSSION: rTMS mediates plasticity in high-order metric levels in the brain and is linked to the spatial distributions of specific neurotransmitter receptors in subjects on the AD spectrum.},
}

@article {pmid42492268,
year = {2026},
author = {Luo, S and Guo, J and Xu, J and Song, J and Dai, Y and Xu, S},
title = {Natural polysaccharides as multi-target therapeutic candidates for Alzheimer's disease: Mechanisms, structure-activity relationships, and translational perspectives.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158585},
doi = {10.1016/j.phymed.2026.158585},
pmid = {42492268},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a systems-level disorder involving amyloid-β (Aβ) deposition, tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and microbiota-gut-brain axis dysregulation. Although previous reviews have summarized the anti-AD effects of natural polysaccharides according to individual pathological pathways, an integrated framework linking polysaccharide structure, gut microbial metabolism, peripheral immune regulation, and central AD pathology remains insufficiently developed.

PURPOSE: This review aims to provide an updated and integrative synthesis of natural polysaccharides as multi-target therapeutic candidates for AD, with particular emphasis on their mechanistic networks, structure-activity relationships, and translational potential.

METHODS: A systematic PubMed search was performed for studies published from January 1, 2016, to June 7, 2026. Eligible studies investigated natural polysaccharides as primary therapeutic interventions in in vivo AD models. Reviews, editorials, purely in vitro studies, studies using polysaccharides solely as drug-delivery carriers, synthetic derivatives, and inseparable compound formulations were excluded. Seventy-four original studies were included for mechanistic and structure-activity analyses.

RESULTS: Natural polysaccharides were found to regulate multiple interconnected AD-related processes, including Aβ production, aggregation, and clearance, tau phosphorylation, redox homeostasis, glial activation, inflammasome signaling, synaptic plasticity, cholinergic function, intestinal barrier integrity, gut microbiota composition, and short-chain fatty acid production. Unlike earlier pathway-based summaries, this review proposes a structure-microbiota-metabolite-barrier-inflammation-redox-brain pathology framework to explain how polysaccharide structural features may determine microbial utilization, metabolite generation, immune modulation, and downstream neuroprotective effects.

CONCLUSION: Natural polysaccharides represent promising multi-target candidates for AD prevention and treatment. Future studies should prioritize structurally defined polysaccharide fractions, causal microbiota validation, pharmacokinetic/pharmacodynamic profiling, biomarker-guided assessment, and rigorously designed clinical trials.},
}

@article {pmid42479714,
year = {2026},
author = {Buard, G and Verny, M},
title = {[Focus on limbic-predominant age-related TDP-43 encephalopathy (LATE)].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {3},
pages = {0},
doi = {10.1684/pnv.2026.1294},
pmid = {42479714},
issn = {2115-7863},
abstract = {In 2019, an international working group described a new clinicopathological entity: limbic-predominant age-related TDP-43 encephalopathy (LATE). Neuropathologically, LATE is characterized by the abnormal accumulation of TDP-43 protein in limbic structures, particularly the hippocampus and parahippocampal regions. Clinically, LATE presents as a slowly progressive, isolated mesiotemporal amnestic syndrome, typically affecting individuals aged over 75 years. Brain MRI usually reveals marked hippocampal atrophy, while FDG-PET may demonstrate medial temporal hypometabolism. A diagnosis of probable LATE requires the exclusion of underlying amyloid pathology, although concomitant Alzheimer's disease pathology is common in older adults. To date, no symptomatic or disease-modifying pharmacological treatment has demonstrated efficacy in LATE. However, its clinical course appears to differ from that of typical Alzheimer's disease, with potentially slower progression and longer preservation of functional independence. LATE therefore represents a common and likely underrecognized cause of memory impairment in older adults, and its identification has important implications for diagnosis, prognosis, and therapeutic decision-making.},
}

@article {pmid42479987,
year = {2026},
author = {Ghorbani, E and Hajihashemi, S and Fahanik-Babaei, J and Nazari, M},
title = {Chronic 40-Hz Light-Emitting Diode (LED) Therapy Attenuates Cognitive and Behavioral Deficits and Modulates BDNF and Caspase-3 Expression in a D-galactose/Aluminum Chloride-Induced Sporadic Alzheimer's-Like Rat Model.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/00207454.2026.2706611},
pmid = {42479987},
issn = {1563-5279},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by gradual deterioration of cognition, synaptic integrity, and neuronal viability. Experimental exposure to D-galactose (D-gal) combined with aluminum chloride (AlCl3) produces oxidative and inflammatory damage within the brain, closely resembling AD-related neuropathology. Photobiomodulation therapy (PBMT) has recently gained attention as a safe, non-pharmacological approach with neuroprotective potential; however, the impact of sustained 40-Hz light-emitting diode (LED) stimulation in this context remains insufficiently explored.

METHODS: In the present study, rats received D-gal (60 mg/kg, i.p.) and AlCl3 (200 mg/kg, oral) for six weeks to induce AD-like changes. The treatment group was exposed to 40-Hz pulsed LED light (425-550 nm, 15 min/session, three times weekly). Behavioral analyses were performed using the elevated plus maze (EPM), novel object recognition (NOR), and passive avoidance (PA) paradigms. Western blotting quantified brain-derived neurotrophic factor (BDNF) and cleaved-caspase-3 expression in whole brain tissue.

RESULTS: D-gal/AlCl3 administration produced anxiety-like behavior, recognition deficits, and impaired memory retention, accompanied by decreased BDNF and elevated caspase-3. Remarkably, 40-Hz LED exposure reversed these alterations, up-regulating BDNF and suppressing caspase-3, in parallel with improvements in cognitive and emotional outcomes.

CONCLUSION: These data suggest that 40-Hz LED stimulation confers neuroprotection in the D-gal/AlCl3-induced AD model, potentially through enhancement of neurotropic signaling and inhibition of apoptosis, supporting its promise as a non-invasive strategy against neurodegenerative decline.},
}

@article {pmid42479989,
year = {2026},
author = {Magee, RG and Xie, SX and Ohm, DT and Rhodes, E and Massimo, L and Van Deerlin, VM and Wolk, DA and Lee, EB and Mcmillan, CT and Irwin, DJ},
title = {Association Between Postmortem Pathologic Burden and the Rate of Clinical Progression in Patients With Frontotemporal Lobar Degeneration.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218278},
doi = {10.1212/WNL.0000000000218278},
pmid = {42479989},
issn = {1526-632X},
mesh = {Humans ; Female ; *Frontotemporal Lobar Degeneration/pathology ; *Disease Progression ; Male ; Middle Aged ; Retrospective Studies ; Aged ; tau Proteins/metabolism ; *Brain/pathology ; DNA-Binding Proteins/metabolism ; Longitudinal Studies ; Autopsy ; },
abstract = {BACKGROUND AND OBJECTIVES: Histopathologic staging of Alzheimer disease has led to validation of imaging techniques that guide diagnosis and treatment. We previously constructed preliminary phases of the sequential progression of TDP-43 and tau to guide similar efforts in behavioral-variant frontotemporal dementia (bvFTD). In this article, we expand this work using digital pathology and longitudinal clinical data to more comprehensively model the relationship between clinical progression and the distribution and severity of postmortem frontotemporal lobar degeneration (FTLD) pathology.

METHODS: In this retrospective cohort study, 101 patients (42% female, median age at symptom onset = 63 years) were selected from the Penn Integrated Neurodegenerative Disease Database and had both longitudinal assessments and primary neuropathologic diagnosis of FTLD-Tau or FTLD-TDP. We used validated methods to quantify the burden of primary pathology from up to 6 cortical regions across hemispheres. FTLD-TDP pathologic phase was constructed from diagnostic pathology data based on published criteria. We tested the association between pathologic metrics and (1) disease duration or (2) the rate of clinic progression measured by 2 independent global measures (Clinical Dementia Rating Scale-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]). Linear regression and linear mixed-effects models were adjusted for hemisphere sampled, sex, age at onset, pathogenic variant status, and pathologic subtype.

RESULTS: Disease duration did not associate with pathologic burden in multiple regression (FTLD-TDP β = 0.01 [-0.06, 0.09]; p = 0.7; FTLD-Tau β = 0.1 [-0.4, 0.7]; p = 0.7). By contrast, mean TDP-43 burden, but not FTLD-Tau burden, was associated with both worse relative CDR-SB (β = 0.1 [0.06, 0.2]; p = 0.0001) and MMSE (β = -0.1 [-0.2, -0.03]; p = 0.009) among all FTLD-TDP patients. TDP-43 phase also associated with worse CDR-SB (β = 0.07 [0.02, 0.1]; p = 0.005) and MMSE (β = -0.2 [-0.3, -0.1]; p = 0.000005). TDP-43 burden (CDR-SB (β = 0.1 [0.03, 0.2]; p = 0.005 and MMSE (β = -0.2 [-0.4, -0.05]; p = 0.009)), but not phase (CDR-SB (β = 0.02 [-0.03, 0.08]; p = 0.4 and MMSE (β = -0.04 [-1, 0.07]; p = 0.5)), associated with relative decline in sensitivity analyses limited to bvFTD.

DISCUSSION: Greater TDP-43 burden was most closely associated with antemortem clinical decline rather than cumulative aggregation through the disease course. These human data suggest that the temporal dynamics of protein aggregation may differ among FTLD proteinopathies, with implications for the interpretation of FTLD-Tau and FTLD-TDP‑specific biomarkers as these are developed.},
}

Humans
Female
*Frontotemporal Lobar Degeneration/pathology
*Disease Progression
Male
Middle Aged
Retrospective Studies
Aged
tau Proteins/metabolism
*Brain/pathology
DNA-Binding Proteins/metabolism
Longitudinal Studies
Autopsy

@article {pmid42482244,
year = {2026},
author = {Bonnì, S and Esposito, R and Mencarelli, L and Di Lorenzo, F and Ricci, F and Di Iulio, F and Savastano, E and Candeo, F and De Masi, F and Coletta, A and Vinci, AC and Ferraresi, M and Mancini, M and Casula, EP and Borghi, I and Spampinato, DA and Maiella, M and Cinnera, AM and Assogna, M and Bruno, M and Nocilli, M and Ferrara, M and Russo, M and Tagliamonte, NL and Ferrari, C and Bertino, S and Calabrò, RS and Maggio, MG and De Luca, R and Burrascano, R and Gjonaj, E and Mirabile, A and De Pasquale, P and d'Avella, A and Quartarone, A and Koch, G},
title = {Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02145-x},
pmid = {42482244},
issn = {1758-9193},
support = {PNRR- MCNT2-2023-12377518//Ministero della Salute/ ; },
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN.

METHODS: This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SoB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively.

SIGNIFICANCE: This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT07075770, registered 10 July 2025.},
}

@article {pmid42482583,
year = {2026},
author = {Yang, SM and Guo, WQ and Dong, WG and Huang, JY and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL},
title = {[Effects of electroacupuncture on motor function and PGC-1α/FNDC5/BDNF pathway in muscle and brain of SAMP8 mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {7},
pages = {887-895},
doi = {10.13702/j.1000-0607.20250437},
pmid = {42482583},
issn = {1000-0607},
mesh = {Animals ; *Electroacupuncture ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Mice ; *Muscle, Skeletal/metabolism ; Male ; *Fibronectins/metabolism/genetics ; Humans ; *Brain/metabolism ; *Alzheimer Disease/genetics/metabolism/therapy/physiopathology ; Signal Transduction ; Motor Activity ; Acupuncture Points ; },
abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on motor function and skeletal muscle morphology in SAMP8 mice, and to explore the mechanisms of EA improving motor dysfunction in Alzheimer's disease from the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/fibronectin type Ⅲ domain-containing protein 5 (FNDC5)/brain-derived neurotrophic factor (BDNF) pathway.

METHODS: SAMP8 mice were randomly divided into model and EA groups, with 9 mice in each group. Nine anti-aging SAMR1 mice were used as control group. In the EA group, "Baihui"(GV20), "Dazhui"(GV14) and "Shenshu"(BL23) were needled with EA for 20 min every day, 8 d as a course of treatment, with an interval of 2 d between courses. A total of 3 courses was proceeded. The motor function of mice was detected by grasping test, swimming test, suspension test and hind limb clamping test. The morphological structure of gastrocnemius muscle was observed by HE staining. The positive expressions of PGC-1α, FNDC5 and BDNF in gastrocnemius muscle were observed by immunohistochemical staining. The expression levels of PGC-1α, FNDC5 and BDNF mRNAs in gastrocnemius muscle and cerebral motor cortex were detected by real-time fluorescence quantitative PCR. The expression levels of PGC-1α, FNDC5 and BDNF proteins in gastrocnemius muscle and cerebral motor cortex were detected by Western blot.

RESULTS: Compared with the control group, the peak grip strength, average and maximum swimming speed, and suspension test score of the model group were significantly decreased (P<0.01), and the hind limb clamping test score was significantly increased (P<0.01). The gastrocnemius muscle fibers were loose and irregularly arranged, the spacing was widened and the cytoplasmic staining was uneven. The positive expression area ratios of PGC-1α, FNDC5 and BDNF in gastrocnemius muscle were significantly decreased (P<0.01), and the relative expression levels of PGC-1α, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly decreased (P<0.01). Compared with the model group, the peak grip strength, average and maximum swimming speed, and suspension test score of the EA group were significantly increased (P<0.01), and the hind limb clamping test score was significantly decreased (P<0.01). The muscle fibers were intact and arranged regularly, the spacing was narrowed, and the cytoplasmic staining was uniform.The positive expression area ratios of PGC-1α, FNDC5 and BDNF were significantly increased (P<0.01), and the relative expression levels of PGC-1α, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly increased (P<0.01, P<0.05). The correlation analysis results of PGC-1α, FNDC5 and BDNF mRNA expression in gastrocnemius and cerebral motor cortex showed a highly positive correlation (r>0.70, P<0.01).

CONCLUSIONS: EA can improve motor dysfunction and skeletal muscle morphology in SAMP8 mice, and its mechanism may be related to up-regulation of PGC-1α, FNDC5 and BDNF expressions in gastrocnemius and cerebral motor cortex.},
}

Animals
*Electroacupuncture
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics
*Brain-Derived Neurotrophic Factor/metabolism/genetics
Mice
*Muscle, Skeletal/metabolism
Male
*Fibronectins/metabolism/genetics
Humans
*Brain/metabolism
*Alzheimer Disease/genetics/metabolism/therapy/physiopathology
Signal Transduction
Motor Activity
Acupuncture Points

@article {pmid42483783,
year = {2026},
author = {Wen, Y and Zhan, S and Duan, Y and Pang, M and Yan, J and Deng, M and Fan, H},
title = {Efficacy and Safety of Mesenchymal Stem Cell Therapy for Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Stem cells and development},
volume = {},
number = {},
pages = {15473287261468404},
doi = {10.1177/15473287261468404},
pmid = {42483783},
issn = {1557-8534},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and effective disease-modifying therapies remain limited. Mesenchymal stem cells (MSCs) have shown therapeutic potential because of their neuroprotective and immunomodulatory properties, but clinical evidence remains inconclusive. We systematically evaluated the efficacy and safety of MSC therapy in AD. Following the PRISMA 2020 guidelines and a PROSPERO-registered protocol (CRD420261329891), we searched PubMed, the Cochrane Library, Embase, Web of Science, CNKI, and Wanfang from inception to March 1, 2026. Clinical studies of patients with primary AD treated with MSCs were included. Outcomes covered cognition, daily function, neuropsychiatric symptoms, biomarkers, imaging findings, and adverse events. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using R. Risk of bias was assessed with the RoB 2 tool, and evidence certainty was assessed with GRADE. Six studies involving 196 patients were included. Overall analyses showed no significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or Mini-Mental State Examination (MMSE) at 12-16 weeks or 24-26 weeks after MSC treatment versus placebo, with substantial heterogeneity. Dose-stratified analyses suggested significant benefits of low-dose MSCs on ADAS-Cog (SMD = -1.33, 95% CI: -2.35 to -0.31) and MMSE (SMD = 2.59, 95% CI: 0.52-4.66). MSC therapy significantly improved Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; SMD = 3.27, 95% CI: 1.79-4.75), but not Neuropsychiatric Inventory (NPI) or Quality of Life in Alzheimer's Disease (QOL-AD) scale. Biomarker analyses showed no significant overall effects on Aβ42 or total tau, although subgroup analyses suggested possible increases in Aβ42 and reductions in total tau at certain doses. Imaging data from two studies indicated potential protective effects on hippocampal atrophy. MSC therapy was generally well-tolerated, although intracerebroventricular administration was associated with more transient adverse events. Evidence certainty was low to very low for most outcomes. MSC therapy for AD appears feasible and relatively safe, with potential cognitive and disease-modifying effects. However, current clinical evidence remains insufficient to confirm its efficacy.},
}

@article {pmid42483925,
year = {2026},
author = {Li, W and Guo, C and Jin, Y and Ji, H and Zhang, L and Li, W and Zhang, W and Fu, L},
title = {Ganoderma sinense Polysaccharides Improve Cognition in a Mouse Model of Alzheimer's Disease by Modulating Gut Microbiota and Short-Chain Fatty Acid Metabolism.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050473800260622054102},
pmid = {42483925},
issn = {1875-5828},
abstract = {INTRODUCTION: The number of patients with Alzheimer's Disease (AD) worldwide is expected to reach 152 million by 2050, but developing an effective AD treatment remains challenging. This study purified two polysaccharides (GSP1 and GSP2) from Ganoderma sinense, a traditional Chinese medicine, and investigated their potential therapeutic effects against AD.

MATERIALS AND METHODS: GSP1 and GSP2 were purified and characterized for key physicochemical properties, including monosaccharide composition and molecular weight. In vitro neuroprotective efficacy was evaluated using glutamate-challenged SH-SY5Y cells. For in vivo assessment, an AlCl₃/D-galactose induced AD mouse model was established to quantify cognitive/memory enhancement. Multiomic analysis of the gut microbiota, Short-Chain Fatty Acid (SCFAs) metabolomics, and behavioural tests were conducted to elucidate the therapeutic mechanisms of GSP1.

RESULTS: Both GSP1 and GSP2 conferred neuroprotection against toxin-induced damage. Notably, GSP1 demonstrated superior efficacy compared with GSP2, significantly enhancing cognitive/ memory performance and reducing amyloid-β plaque deposition. Furthermore, GSP1 changed gut microbial diversity and SCFA metabolic profiles. Critical genus-level correlations emerged: Turicibacter, Jeotgalicoccus, and Staphylococcus were positively associated with therapeutic outcomes, whereas Odoribacter was negatively associated.

DISCUSSION: Natural polysaccharides, particularly GSP1, demonstrate therapeutic potential against AD by modulating gut microbiota. Mechanistically, this effect is linked to reshaping microbial communities and affecting the production of neuroprotective SCFAs. Although these findings position GSP1 as a promising AD therapeutic candidate, deeper exploration of gut-brain axis mechanisms remains essential for clinical translation.

CONCLUSION: GSP1 emerges as a promising therapeutic candidate for AD, offering a new approach to developing AD-targeted pharmaceuticals and nutraceuticals.},
}

@article {pmid42484409,
year = {2026},
author = {Tulloch, R and Gaffiero, D},
title = {Menopause, brain health and hormone replacement therapy: gaps in knowledge and policy solutions from a Scottish perspective.},
journal = {Post reproductive health},
volume = {32},
number = {1},
pages = {77-81},
doi = {10.1080/20533691.2026.2631221},
pmid = {42484409},
issn = {2053-3705},
mesh = {Humans ; Female ; Scotland ; *Menopause/physiology/psychology ; Women's Health ; *Health Policy ; *Brain/physiology ; *Hormone Replacement Therapy ; Health Knowledge, Attitudes, Practice ; Alzheimer Disease/prevention & control ; Primary Health Care ; Quality of Life ; },
abstract = {PURPOSE: This commentary argues for the systematic integration of brain health into menopause care and policy in the United Kingdom (UK). Using Scotland as a strategically bounded case study, it examines persistent knowledge gaps among women and primary care professionals and their implications for equitable menopause care.

KEY ISSUES: Menopause involves significant neuroendocrine changes that affect brain metabolism, structure, and cognition, contributing to women's disproportionate Alzheimer's disease risk. Although hormone replacement therapy may alleviate neurological and cognitive symptoms - and may offer neuroprotective benefits when initiated early - clinical uncertainty, stigma, and inconsistent guidance continue to delay recognition, support, and treatment. These gaps translate into avoidable cognitive decline, reduced quality of life, and marked inequities in access to menopause care.

IMPLICATIONS: Targeted primary care training, coherent public communication, and UK-specific investment in evidence-based menopause services are urgently required. This programme of research is situated within Scotland as a strategically bounded, devolved health system, allowing for a focused examination of how brain health is addressed within menopause policy and practice. By embedding brain health within Scotland's Women's Health Plan, the findings will inform future comparative and UK-wide research and contribute to the development of equitable, person-centred, and brain-health informed menopause care across the lifespan.},
}

Humans
Female
Scotland
*Menopause/physiology/psychology
Women's Health
*Health Policy
*Brain/physiology
*Hormone Replacement Therapy
Health Knowledge, Attitudes, Practice
Alzheimer Disease/prevention & control
Primary Health Care
Quality of Life

@article {pmid42484748,
year = {2026},
author = {Abroumand Gholami, A and Ghadiminia, N and Akhrorova, S and Kubaev, A and Agamurodov, S and Salomova, F},
title = {Correspondence: Erythrina caffra in cadmium-induced Alzheimer's-like pathology: A new candidate or a familiar pattern?.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42484748},
issn = {1573-4978},
mesh = {*Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; Animals ; *Cadmium/toxicity ; *Plant Extracts/pharmacology/therapeutic use ; *Erythrina/chemistry/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Rats ; Oxidative Stress/drug effects ; Disease Models, Animal ; },
abstract = {Cadmium neurotoxicity has been increasingly linked to neurodegenerative processes, and plant-derived compounds are being explored for their protective potential. The recent study by Ed-Day and colleagues investigated the neuroprotective effects of Erythrina caffra seed extract in a cadmium-induced Alzheimer's-like model in rats, reporting improvements in memory, cholinergic function, oxidative stress, and neuroinflammation. Four principal concerns are identified: (1) treatment protocol ambiguity, use of young rats to model an age-related disease, and unclear prevention-versus-therapy distinction; (2) memantine as positive control, mechanistically mismatched with cadmium toxicity pathways; (3) claim of Alzheimer's-like pathology without measuring Aβ plaques and tau tangles; and (4) no cadmium quantification in tissues or biofluids, leaving the mechanism, direct neuroprotection versus reduced bioavailability, unresolved. While the study offers promising preliminary evidence for the neuroprotective potential of E. caffra, its translational significance is constrained by these methodological and interpretative limitations. Addressing these concerns in future investigations would strengthen the evidence base for this medicinal plant's therapeutic potential.},
}

*Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism
Animals
*Cadmium/toxicity
*Plant Extracts/pharmacology/therapeutic use
*Erythrina/chemistry/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Humans
Rats
Oxidative Stress/drug effects
Disease Models, Animal

@article {pmid42485607,
year = {2026},
author = {Chen, Y and Chen, A and Power, MC and Grodstein, F and Kapasi, A and Capuano, AW and Lange-Maia, BS and Moghtaderi, A and Stapp, EK and Bhattacharyya, J and Shah, RC and Barnes, LL and Bennett, DA and James, BD},
title = {Associations of Alzheimer Disease and Related Dementia Neuropathologies With Timely Diagnosis of Dementia in Healthcare Settings.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218352},
doi = {10.1212/WNL.0000000000218352},
pmid = {42485607},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/pathology/diagnosis ; Aged, 80 and over ; Retrospective Studies ; *Dementia/diagnosis/pathology ; Aged ; *Brain/pathology ; United States ; Cohort Studies ; Medicare ; },
abstract = {BACKGROUND AND OBJECTIVES: A timely diagnosis of dementia may provide valuable time for treatment and planning, yet underdiagnosis is common. This study investigated the relationship between presence of dementia pathologies and timeliness of dementia diagnosis by healthcare providers.

METHODS: This was a retrospective study using 5 cohorts at Rush Alzheimer's Disease Center. We included participants who met all of the following criteria: (1) incident dementia based on annual cohort assessments, (2) linkage to Medicare records, and (3) a completed postmortem brain autopsy. Postmortem neuropathologic examinations identified the presence of AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), vascular pathologies, and neocortical Lewy bodies (LBs). In linked Medicare data, we defined timely diagnosis as the presence of claims with dementia diagnoses within 3 years before or 1 year after the cohort-based dementia onset. We used logistic regressions to quantify associations of neuropathology markers with timely diagnosis vs underdiagnosis.

RESULTS: Of the 500 eligible participants (71% female, 95% non-Latino White, mean [SD] age at cohort dementia onset = 88 [7] years, mean [SD] years from onset to death = 4 [3]), only 54% received a timely diagnosis. After controlling for demographics, time to death, and other neuropathologies, a pathologic diagnosis of AD (OR = 1.91, 95% CI 1.21-3.00) and moderate/severe LATE-NC pathologies (OR = 1.83, 95% CI 1.25-2.68) were independently associated with higher odds of timely diagnosis. Moderate/severe vascular pathologies (OR = 0.94, 95% CI 0.55-1.59) and neocortical LB pathologies (OR = 1.00, 95% CI 0.64-1.55) were not significantly associated with receipt of a timely diagnosis. In a separate multivariable logistic regression, we found that participants with 3 or 4 neuropathologies present had an over 2-fold increase in odds of timely diagnosis (OR = 2.24, 95% CI 1.32-3.82), compared with those with 1 or no neuropathology.

DISCUSSION: In deceased older adults with cohort-determined incident dementia, the healthcare system was twice as likely to capture those with pathologic diagnosis of AD, moderate/severe LATE-NC, and more than 3 copathologies in a timely manner. While findings from this predominantly White and highly educated sample warrant replication in broader population, this study is an important initial step toward understanding biological correlates of timely diagnosis of dementia.},
}

Humans
Female
Male
*Alzheimer Disease/pathology/diagnosis
Aged, 80 and over
Retrospective Studies
*Dementia/diagnosis/pathology
Aged
*Brain/pathology
United States
Cohort Studies
Medicare

@article {pmid42486010,
year = {2026},
author = {Li, X and Li, S and Su, J and Zheng, F and Li, S and Zhao, X and Chen, D and Yan, J and Xia, C},
title = {Merocyanine derivatives as theranostic agents for cognitive improvement and real-time imaging of amyloid-β in APP/PS1 transgenic mice.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {363},
number = {Pt 1},
pages = {128458},
doi = {10.1016/j.saa.2026.128458},
pmid = {42486010},
issn = {1873-3557},
abstract = {Amyloid-β (Aβ) is widely recognized as a biomarker for the diagnosis and treatment of Alzheimer's Disease (AD). In our previous work, a series of merocyanine fluorescent probes were designed, synthesized and evaluated for the imaging of Aβ plaques. Here, we further identified the representative probe D4, which not only demonstrates the characteristics of a highly sensitive fluorescent probe for real-time imaging of Aβ content in the brain of APP/PS1 mice, but also exhibited the ability to treat AD, including inhibition of Aβ aggregation (inhibition rate: 89.5%), antioxidant activity (3.4 times that of Trolox); AChE inhibitory activity (IC50 = 0.5 ± 0.0 μM) and the capacity to cross the BBB (Pe = 8.6 ± 0.7). Additionally, D4 dramatically attenuates Aβ-induced SH-SY5Y cell death by preventing the generation of ROS, and intravenous administration of 0.5 mg/kg D4 for 15 days significantly improved the cognitive ability of 7-month-old APP/PS1 mice by protecting hippocampal and cortex neurons from necrosis, attenuating oxidative stress in the hippocampus and cortex, and reducing Aβ burden deposition. These findings strongly suggest that D4 owns a high theranostic potential for treating AD.},
}

@article {pmid42486320,
year = {2026},
author = {Dilip, PI and Daksh, R and Sharma, P and Khanna, S and Bojja, SL and Singh, AK and Nampoothiri, M},
title = {Repressor Element 1 Silencing Transcription Factor as a central regulator of autophagy and neuroinflammation in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179168},
doi = {10.1016/j.ejphar.2026.179168},
pmid = {42486320},
issn = {1879-0712},
abstract = {Repressor element-1 silencing transcription factor (REST) is a critical epigenetic regulator involved in multiple cellular processes, including apoptosis, autophagy, and neuronal survival. By modulating the expression of neuronal and stress-response genes, REST contributes significantly to neuroprotection. REST is predominantly localised in the nucleus; however, in Alzheimer's Disease (AD), nuclear REST is reduced, leading to transcriptional dysregulation and contributing to AD pathology. The low levels of REST are associated with defective autophagy flux, including mitochondrial dysfunction and enhanced vulnerability to toxic protein aggregates, causing AD and other neurodegenerative disorders. Recent research shows that REST suppresses several apoptotic genes, modulating neuroinflammatory signalling and regulates autophagy. The specific regulatory mechanism of REST suggests new strategies for the prevention and treatment of AD and ageing. Despite REST's unique functions and importance in AD, its precise role and the molecular mechanisms underlying REST-mediated signalling pathways have not been comprehensively reviewed. The purpose of this review is to provide an overview of the structural and functional characteristics of REST, explore the mechanisms underlying REST-mediated autophagy, neuroinflammation and apoptosis in AD and discuss the emerging therapeutic implications of targeting REST.},
}

@article {pmid42487022,
year = {2026},
author = {Xu, W and Chen, J and Zhou, Y and Liu, C and Han, Y and Zheng, K},
title = {Comparative efficacy and safety of photobiomodulation, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation in Alzheimer's disease: a network meta-analysis of randomized controlled trials.},
journal = {Lasers in medical science},
volume = {41},
number = {1},
pages = {},
pmid = {42487022},
issn = {1435-604X},
support = {82371442//National Natural Science Foundation of China/ ; 2020YFC2004803//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/adverse effects/methods ; *Transcranial Magnetic Stimulation/adverse effects/methods ; Randomized Controlled Trials as Topic ; *Low-Level Light Therapy/adverse effects/methods ; Treatment Outcome ; Cognition ; Cognitive Enhancement ; Bayes Theorem ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which current pharmacological therapies provide only modest and transient benefits, underscoring the need for effective non-pharmacological interventions. Non-invasive brain stimulation (NIBS), including photobiomodulation (PBM), transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS), is a promising approach. This study compared the efficacy, feasibility, and safety of PBM, tDCS, and rTMS in AD. We conducted a Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs), prospectively registered in PROSPERO (CRD420251006868) and reported according to PRISMA-NMA. The primary outcome was global cognitive performance, assessed by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were feasibility and safety, evaluated by dropout rates and adverse events, respectively. A total of 34 studies, comprising 35 RCTs (n = 1,559), were included, with one study contributing two independent randomized controlled trials. All three interventions improved global cognitive performance compared with control. PBM showed the highest estimated effects on both MMSE (MD = 3.14, 95% CrI: 1.71 to 4.60) and ADAS-Cog (MD = - 8.01, 95% CrI: -12.82 to - 3.13). In indirect comparisons, PBM was superior to rTMS for ADAS-Cog (MD = - 5.24, 95% CrI: -10.23 to - 0.12), while the MMSE comparison narrowly missed statistical significance (MD = 1.57, 95% CrI: -0.02 to 3.18). These findings were generally consistent across subgroups stratified by baseline cognition and intervention duration. PBM tended to rank highest for cognitive improvement with feasibility and safety comparable to tDCS and rTMS in AD. These findings support the therapeutic potential of PBM, and large-scale RCTs are needed to guide individualized treatment strategies, with implications for clinical decision-making in geriatric care.},
}

Humans
*Alzheimer Disease/therapy
*Transcranial Direct Current Stimulation/adverse effects/methods
*Transcranial Magnetic Stimulation/adverse effects/methods
Randomized Controlled Trials as Topic
*Low-Level Light Therapy/adverse effects/methods
Treatment Outcome
Cognition
Cognitive Enhancement
Bayes Theorem

@article {pmid42487544,
year = {2026},
author = {Zhou, J and Li, S and Liu, H and Sun, Y and Wang, Z},
title = {The Effectiveness of Animal-Assisted Interventions for People Living With Dementia: An Overview of Systematic Reviews and Meta-Analysis.},
journal = {International journal of nursing practice},
volume = {32},
number = {4},
pages = {e70172},
pmid = {42487544},
issn = {1440-172X},
support = {72274007//National Natural Science Foundation of China/ ; LJRC22YB03//Incubation Fund for Scientific Research and Innovation of Leading Talents of Unnamed Nursing of Peking University/ ; XJRC-2025-JY-YJ-GX-QNQZ-068//Xinjiang Talent Development Fund/ ; },
mesh = {*Dementia/therapy/psychology ; Humans ; *Animal Assisted Therapy ; Animals ; Quality of Life ; Systematic Reviews as Topic ; Activities of Daily Living ; },
abstract = {AIMS: This overview aims to provide high-quality evidence synthesis of animal-assisted interventions (AAIs) among people living with dementia.

BACKGROUND: Dementia has become the seventh leading cause of death in the world. Unfortunately, currently effective pharmacological interventions remain elusive. As a non-pharmacological treatment, AAI is gaining more attention while the effectiveness of AAI for people living with dementia remains unclear.

METHODS: EMBASE, PubMed, Cochrane Library, CINAHL, CNKI, VIP, CBM and Wanfang databases were searched from inception to March 2026. The AMSTAR2 was used to assess the methodological quality of the included reviews. Meta-analysis was conducted using STATA 16 for the original studies identified from the included reviews. Evidence quality of main outcomes was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.

RESULTS: Sixteen systematic reviews were included in the overview. A significant improvement was found in depression among dementia patients, but not in agitation, quality of life (QOL), cognition and activities of daily living (ADL).

CONCLUSIONS: There is moderate evidence that AAI has positive effects on depression for people living with dementia. Despite searches, no sufficient evidence has been found to substantiate the positive effects of AAI on other outcomes in people living with dementia. Due to the small number of studies, small sample sizes and significant heterogeneity, more randomised controlled trials with large samples are needed.},
}

*Dementia/therapy/psychology
Humans
*Animal Assisted Therapy
Animals
Quality of Life
Systematic Reviews as Topic
Activities of Daily Living

@article {pmid42487594,
year = {2026},
author = {Lonlab, K and Nitjapol, A and Thummayot, S and Tiyaboonchai, W and Jumnongprakhon, P},
title = {Targeting Aβ25-35-Induced Neuronal Senescence-Like Features Using Curcumin-Loaded Solid Self-Emulsifying Drug Delivery Systems.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098440081260430205824},
pmid = {42487594},
issn = {1874-6128},
abstract = {INTRODUCTION: Curcumin is widely recognized for its anti-neurodegenerative properties. However, its clinical utility is hindered by poor aqueous solubility and low bioavailability. To address these limitations, Curcumin-loaded Solid Self-Emulsifying Drug Delivery Systems (C-SSEDDS) have been formulated to improve pharmacokinetics and neuronal targeting. Despite these advancements, the molecular mechanisms underlying curcumin in Alzheimer's Disease (AD)-related neuronal senescence remain poorly understood. Therefore, this study provides novel molecular insights into the therapeutic potential of C-SSEDDS for targeting neuronal senescence- like features in the AD context.

METHODS: An in vitro model of neuronal senescence-like features was established by exposing SK-N-SH cells to 0.075 μM Aβ25-35 for 24 hours, resulting in a 20-30% decline in cell viability. Subsequently, cells were post-treated with C-SSEDDS at optimized non-toxic concentrations (0.1, 1, and 10 μg/mL curcumin equivalent) and 10 μg/mL commercial curcumin for 24, 48, and 72 hours in Aβ25-35-free media. The study comprehensively assessed cell viability, morphological alterations, and key biomarkers associated with neuronal senescence-like features, including senescence- associated beta-galactosidase (SA-β-gal) positive cells, Reactive Oxygen Species (ROS) levels, NLRP3, Sirt-1, and synaptophysin expression.

RESULTS: C-SSEDDS post-treatment significantly improved cell viability, reduced apoptotic cells, and decreased SA-β-gal positive cells in Aβ25-35-induced senescence-like SK-N-SH cells compared to the untreated Aβ25-35 group. It also effectively decreased intracellular ROS level and NLRP3 expression, and markedly upregulated Sirt-1 and synaptophysin expression. Notably, CSSEDDS demonstrated therapeutic efficacy superior to commercial curcumin and comparable to N-acetylcysteine (NAC).

DISCUSSION: In SK-N-SH cells exhibiting senescence-like features, the C-SSEDDS formulation effectively counteracts Aβ25-35-induced damage. It mitigates key drivers of cellular stress, including oxidative stress, inflammation-related markers, and apoptosis, while also enhancing Sirt-1 activity and promoting synaptic plasticity.

CONCLUSION: C-SSEDDS demonstrates significant potential as a promising therapeutic strategy against Aβ25-35 -induced neuronal stress and senescence-like changes in AD.},
}

@article {pmid42488183,
year = {2026},
author = {Singhal, M and Lin, J and Delehanty, M and Karimi, A and Rittner, L and Bento, M},
title = {Geographic and demographic gaps in publicly available Alzheimer's disease datasets: A large language model-based discovery and analysis.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261470698},
pmid = {42488183},
issn = {2055-2076},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions worldwide, and researchers heavily rely on datasets for diagnosis and treatment. Identifying relevant datasets is challenging due to data gaps and bias related to the demographics and geographic origin.

METHOD: We investigated AD data gaps by identifying and manually curating publicly accessible AD datasets containing imaging and/or tabular data. We also extracted key information such as data availability, geographic location, and participant demographics. We used five Large Language Models (LLMs) to identify AD datasets, allowing us to explore potential datasets while also evaluating retrieval consistency across models.

RESULT: We identified 24 publicly accessible AD datasets (open access or controlled access via registration). These datasets enabled us to emphasize three critical gaps: (1) variability in AD dataset retrieval, as observed through differences in LLM outputs, related to dataset visibility and accessibility; (2) geographical imbalance, with North America contributing 55.6% of datasets, US alone 66.7%, followed by Europe at 36.1%, and smaller shares from South America 11.1%, Asia 8.3%, and Africa 2.8%; and (3) demographic deficits, with the majority of datasets predominantly White, as 9 of 24 had over 80% White participants. Among the seven datasets that reported any Black participant representation, the proportion of Black participants ranged from 15.3% to 18.8%.

CONCLUSION: These findings reveal significant disparities in the availability and retrieval of AD datasets, with most data concentrated in Western countries and critical gaps in demographic representation. LLMs show inconsistent retrieval, particularly for newer, smaller, or region-specific datasets, which may perpetuate existing biases.},
}

@article {pmid42475384,
year = {2026},
author = {Ma, L and Wang, D and Li, Z and Ye, G and Chen, M},
title = {Exosomal gene-based predictive model and therapeutic target identification for Alzheimer's disease: A bioinformatics analysis.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354014},
pmid = {42475384},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; Humans ; *Computational Biology/methods ; Molecular Docking Simulation ; *Exosomes/genetics/metabolism ; Gene Regulatory Networks ; Gene Expression Profiling ; Databases, Genetic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative central nervous system disorder characterized by progressive cognitive and behavioral impairment. As nanoscale intercellular communication vesicles that carry AD-related pathological molecules, exosomes are promising biomarkers and therapeutic carriers for AD. In this study, we downloaded AD-related gene expression profiles and clinical data from the Gene Expression Omnibus (GEO) database (datasets GSE138260, GSE29378, GSE36980, and GSE5281). Through a series of bioinformatics analyses, clinical predictive model construction, pharmacological network analysis, and molecular docking simulations, we developed an exosomal gene-based predictive model for AD pathogenesis and identified potential pharmacological networks and molecular docking targets for AD treatment.

MATERIALS AND METHODS: AD-related gene expression and clinical data were retrieved from the GEO database. Bioinformatics analyses, clinical model construction, drug-gene network analysis, and molecular docking were subsequently performed to explore exosomal gene models for predicting AD pathogenesis, as well as potential pharmacological networks and molecular docking targets for AD therapy.

RESULTS: A five-exosomal-gene predictive model was established, comprising CD44, CXCR4, TUBB, PSMA5, and PSMB3. Pharmacological network analysis of these five genes revealed their significant associations with chelidonine, 2-chloro-1,4-dinitrobenzene, oxazolone, phencyclidine, thioridazine, and etodolac. Further molecular docking simulations identified key binding targets, including R41, Y42, R78, Y79, C77, I88, C97, A98, I96, I72, L70, E67, G103, I91, and T102.

CONCLUSIONS: Our comprehensive analyses successfully established a reliable exosomal gene-based model for predicting AD pathogenesis, and identified relevant pharmacological networks and core molecular docking targets, providing novel insights for AD diagnosis and targeted therapy.},
}

*Alzheimer Disease/genetics/drug therapy/metabolism
Humans
*Computational Biology/methods
Molecular Docking Simulation
*Exosomes/genetics/metabolism
Gene Regulatory Networks
Gene Expression Profiling
Databases, Genetic

@article {pmid42475614,
year = {2026},
author = {Jarrell, L and Vanhoy, S},
title = {Doll therapy: Innovative treatment for patients with Alzheimer disease to improve patient and staff safety in a hospital setting.},
journal = {Nursing},
volume = {56},
number = {8},
pages = {56-61},
doi = {10.1097/NSG.0000000000000419},
pmid = {42475614},
issn = {1538-8689},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; *Patient Safety/standards ; Aged ; *Play Therapy/methods ; Accidental Falls/prevention & control ; Aged, 80 and over ; },
abstract = {BACKGROUND: Patients with Alzheimer disease may display negative neuropsychiatric symptoms that can pose patient safety risks.. Doll therapy is described in the literature as a successful diversional activity for these patients.

PURPOSE: This project aimed to provide doll therapy to patients with Alzheimer disease at their facility to reduce neuropsychiatric symptoms, improve patient safety, patient outcomes, and the patient and family experience, and to positively impact the health care team's experience when caring for this patient population.

METHODS: A total of 55 patients with a diagnosis of Alzheimer disease participated in the doll therapy program. Quantitative and qualitative data were collected and analyzed. These included patient's behavior prior to doll therapy and the patient's response to doll therapy.

RESULTS: Patients experienced a sense of purpose and comfort, as well as decreased risk for falls, physical workplace violence events, and being placed in restraints as a result of doll therapy.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
Male
*Patient Safety/standards
Aged
*Play Therapy/methods
Accidental Falls/prevention & control
Aged, 80 and over

@article {pmid42476460,
year = {2026},
author = {Fowler, CF and Osipyan, E and Devenyi, GA and Madularu, D and Breitner, J and Near, J},
title = {Early treatment with naproxen alters hippocampal metabolites in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106226},
doi = {10.1016/j.neuint.2026.106226},
pmid = {42476460},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is characterized by the appearance of brain pathology decades prior to clinical symptoms. The pre-symptomatic phase of AD provides opportunity for early detection and intervention. One early intervention that has been proposed is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. However, evidence suggests that effects of naproxen intervention differ with stage of the disease, and the optimal intervention time is not clear. Accordingly, in this study, we investigated the impact of the timing of naproxen treatment in a rat model of AD. We used the TgF344-AD rat model of AD which develops characteristic pathological features of human AD, including abundant amyloid plaque pathology, astrogliosis, and microgliosis by 6 months of age, and neurofibrillary tangles and neuronal loss by 16 months of age. We examined the effects of naproxen treatment beginning at 1, 4, and 10 months of age in transgenic (Tg) animals and their wild-type (WT) littermates. We used longitudinal in vivo magnetic resonance spectroscopy (MRS) to study the impact of naproxen treatment on hippocampus neurochemistry. Previous studies have used MRS to non-invasively characterize the trajectory of altered hippocampal neurochemistry across the lifespan in the TgF344-AD rat model. In the current study, we employed MRS at 4, 10, and 16 months, i.e. prior to or after the appearance of amyloidosis and gliosis (6 months) and tau pathology (16 months), respectively, in Tg animals. Naproxen treatment altered neurochemistry in Tg animals only if administered beginning at 1 or 4 months of age, mitigating an otherwise observed increase in total choline and decrease in taurine. A more subtle effect was observed on the otherwise-expected increase in myo-inositol. These results highlight the possibility that earlier naproxen intervention could have distinct neurochemical effects compared to delayed treatment, though mechanistic implications remain to be clarified. Moreover, these findings support the use of MRS as a useful non-invasive method of monitoring treatment-related changes in neurochemistry in transgenic animal models.},
}

@article {pmid42477703,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Associations of Ginkgo biloba extract exposure with 12-month cognitive trajectories in amyloid PET-positive mild cognitive impairment and Alzheimer's disease: a pooled retrospective cohort study.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05469-1},
pmid = {42477703},
issn = {2662-7671},
support = {HI22C0667//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) show considerable heterogeneity in treatment response, underscoring the need for individualized therapeutic approaches. Ginkgo biloba extract is commonly used in cognitive disorders, but its efficacy in amyloid biomarker-confirmed populations remains unclear. To evaluate the association between Ginkgo biloba extract exposure and 12-month cognitive and functional change patterns in amyloid PET-positive MCI/AD, and to assess whether baseline plasma MDS-OAβ (amyloid oligomerization tendency) is associated with cognitive trajectory subgroup membership.

METHODS: In this 12-month retrospective study, 165 drug-naïve amyloid PET-positive patients (83 with documented Ginkgo biloba extract use in routine care and 82 without documented Ginkgo use) were assessed for changes in Korean Mini-Mental State Examination (K-MMSE-2), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Korean Instrumental Activities of Daily Living (K-IADL), and plasma MDS-OAβ levels. K-means clustering was used to define three cognitive trajectory subgroups, and exploratory one-vs-rest adjusted logistic regression analyses were performed to examine baseline variables associated with trajectory group membership.

RESULTS: Three cognitive trajectories were identified: Improver (n = 36), Stabler (n = 113), and Decliner (n = 16). Compared with patients without documented Ginkgo use, patients with documented Ginkgo exposure showed significantly greater cognitive gains (ΔK-MMSE-2 + 1.42 vs. - 0.30, p = 0.012), less IADL decline (p < 0.001), and greater reductions in MDS-OAβ levels (p < 0.001). Baseline plasma MDS-OAβ did not significantly differ among the trajectory groups and was not interpreted as a robust independent predictor of trajectory membership. Ginkgo use differed significantly across trajectory groups and was least frequent in the Decliner group.

CONCLUSIONS: In this amyloid PET-positive MCI/AD cohort, Ginkgo biloba extract exposure was associated with more favorable 12-month cognitive, functional, and plasma MDS-OAβ changes. However, baseline MDS-OAβ should be regarded as an exploratory biomarker rather than a validated predictor of improvement or Ginkgo-related benefit.},
}

@article {pmid42478598,
year = {2026},
author = {Martens, CR and Decker, KP and DeConne, TM and Sanjana, F and Horvat, F and Rizzi, NA and Awad, C and Habash, E and Hobson, JC and Kramer, MK and Armstrong, ML and Reisdorph, N and Pohlig, RT and Lanzi, AM and Johnson, CL and Cohen, ML and Ellison, JM},
title = {A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71605},
pmid = {42478598},
issn = {1552-5279},
support = {K01AG054731/AG/NIA NIH HHS/United States ; P20GM113125/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Pilot Projects ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Aged ; Double-Blind Method ; Female ; *Niacinamide/analogs & derivatives/therapeutic use/administration & dosage ; Male ; *Dietary Supplements ; Cerebrovascular Circulation/drug effects ; Pyridinium Compounds ; Neuropsychological Tests ; Cognitive Enhancement ; NAD/blood ; *Amnesia/drug therapy ; Blood Pressure/drug effects ; Treatment Outcome ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD[+]) may elevate risk of Alzheimer's disease.

METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD[+] precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).

RESULTS: 42 participants completed the study (NR = 22, placebo = 20). Adherence was similar between groups with no serious adverse effects. Blood NAD[+] increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). Exploratory analyses revealed potential increases in regional CBF, particularly in the hippocampus.

DISCUSSION: NR effectively raises NAD[+] in people with MCI but does not improve cognitive function, total CBF, or blood pressure over 12 weeks. Future studies should investigate regional effects on CBF over longer treatment durations.},
}

Humans
Pilot Projects
*Cognitive Dysfunction/drug therapy/diagnostic imaging
Aged
Double-Blind Method
Female
*Niacinamide/analogs & derivatives/therapeutic use/administration & dosage
Male
*Dietary Supplements
Cerebrovascular Circulation/drug effects
Pyridinium Compounds
Neuropsychological Tests
Cognitive Enhancement
NAD/blood
*Amnesia/drug therapy
Blood Pressure/drug effects
Treatment Outcome
Aged, 80 and over

@article {pmid42478899,
year = {2026},
author = {Zhang, N and Chen, W and Wang, M},
title = {The liver-brain axis: A multidimensional regulatory network implicated in Alzheimer's disease pathogenesis and clinical implications.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70262},
pmid = {42478899},
issn = {2576-2095},
support = {Seed Program (YYZZ202409)//Capital Medical University Affiliated Beijing Friendship Hospital/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition. The liver-brain axis underscores the central role of the liver in modulating cognitive function through multidimensional regulatory mechanisms. As a core metabolic and detoxification organ, the liver also helps maintain cerebral homeostasis via pathways including the urea cycle, antioxidant systems, ketone body metabolism, and bile acid regulation. Dysfunction of these processes may lead to ammonia accumulation, exacerbated oxidative stress, and Aβ clearance, thereby accelerating the pathological progression of AD. Liver-derived factors such as apolipoprotein E (APOE), C-reactive protein (CRP), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (IGF-1) significantly increase the risk of AD through dual mechanisms-inhibiting Aβ clearance and activating neuroinflammation, thereby directly affecting cognitive function via modulation of inflammation, metabolism, and blood-brain barrier (BBB) integrity. Neural interfaces formed by the hypothalamic-pituitary-target gland axis and the vagus nerve enable communication from the liver to the brain, with emerging evidence also supporting a reverse influence from the brain to the liver. Emerging technologies such as molecular tracing and nanocarriers provide new tools for deciphering dynamic interactions within the liver-brain axis. Liver-targeted metabolic interventions show potential for reversing cognitive impairment. Unlike previous reviews that mainly focused on single pathways, this review conceptualizes the liver-brain axis as a multidimensional regulatory network in AD. By clearly linking network nodes to potential therapeutic interventions, it provides us with a novel framework that not only describes the various mechanisms but also focuses on identifying actionable targets for disease prevention and treatment.},
}

@article {pmid42479540,
year = {2026},
author = {Zhang, J and Yu, P and Xu, M and Liang, F and Chen, Y and Dong, Y and Zhang, Y and Yu, S and Hua, F and Otu, HH and Libermann, TA and Inouye, SK and Marcantonio, ER and Yang, G and Xie, Z},
title = {Anesthesia and surgery induce sex-dependent Tau phosphorylation and behavior changes in aged mice.},
journal = {Anesthesiology},
volume = {},
number = {},
pages = {},
doi = {10.1097/ALN.0000000000006261},
pmid = {42479540},
issn = {1528-1175},
abstract = {BACKGROUND: Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer's disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remain largely undetermined.

METHODS: Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery under general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and GSK3β activity were measured in lungs, blood, and brain tissues of aged mice using nanoneedle technology, Western blot, immunohistochemistry, RT-PCR and others. Postoperative delirium-like behavior was assessed using a battery of behavioral tests (buried food, open filed and Y maze). To explore causality, we performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice.

RESULTS: Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29±0.16 fold versus 1.15±0.71 fold, P<0.01), blood, and brain tissues of aged female, but not male, mice compared to control condition, leading to postoperative delirium-like behavior, as evidenced by increases in the composite Z score (3.74±1.46 versus 0.60±1.17, P<0.01), in the aged female, but not male, mice. Anesthesia/surgery elevated inflammatory markers and GSK3β activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes following anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery-induced elevation of Tau-PT217 amounts and behavior changes.

CONCLUSIONS: Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.},
}

@article {pmid42473218,
year = {2026},
author = {Keskin, A and Mogulkoc, R and Baltaci, AK},
title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575484348260702044851},
pmid = {42473218},
issn = {1875-5607},
abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).},
}

@article {pmid42473227,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Rodrigues, FCP and Cavalcante, LL and Payão, SLM and Tavares, AR and Forlenza, OV and de Godoy, MF and Filho, GMA},
title = {Cardiovascular Comorbidities with Alzheimer's Disease: A Systematic Review and Meta-analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050468989260629094050},
pmid = {42473227},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease stands as the most prevalent form of dementia, characterized by a progressive decline in cognitive function and memory. Numerous risk factors have been linked to its development, creating a complex interplay of influences. In this study, we aim to delve into the relationship between cardiovascular disease and Alzheimer's disease, exploring how conditions affecting heart health may impact the onset and progression of this debilitating neurological disorder. Through this research, we could find potential connections that inform prevention strategies and therapeutic approaches.

MATERIALS AND METHODS: We adopted the PRISMA guidelines and defined the PECOS framework as follows: Population (P) = individuals; exposure (E) = cardiovascular disease; comparison (C) = without cardiovascular disease; outcome (O) = Alzheimer's disease; and study design(S) = all kinds of studies with an association between cardiovascular disease and Alzheimer's disease without time limits. A meta-analysis was conducted using case-control, cohort, and genetic studies to estimate Odds Ratios (ORs) or Hazard Ratios (HRs).

RESULTS: The pooling of data in meta-analysis demonstrated that a person with any Cardiovascular Disease (CVD), Heart Failure (HF), Coronary Artery Disease (CAD), Atrial Fibrillation (AF), Hypertension (HTN), and Myocardial Infarction (MI) had more risk of developing Alzheimer's disease [CVD: HR = 1.30 (CI: 1.27-1.33) / HF: HR = 1.63 (CI: 1.37-1.94) / CAD: HR = 1.43 (CI: 1.40-1.46) / AF: HR = 1.38 (CI: 1.34-1.42) / HTN: HR = 1.22 (CI: 1,10-1.35) / MI: HR = 1.07 (CI: 1,01-1.13)]. Cross-sectional studies demonstrated an association between cardiovascular diseases and Alzheimer's disease [OR = 1.29 (CI: 1.23-1.35)]. Mendelian randomization meta-analysis did not demonstrate a causal relation between cardiovascular disease and Alzheimer's disease [AF: OR = 1.03 (CI: 1.00-1.01) / HF: OR = 1.00 (CI: 0,79-1.36)]. A Mendelian randomization meta-analysis demonstrated that a person with AD had a higher risk of developing myocardial infarction [OR = 1.07 (CI: 1.03-1.10)].

DISCUSSION: This review examines the connection between AD and CVD, noting that HF increases the risk of developing AD with a hazard ratio of 1.63. It suggests that altered brain perfusion and hypoxia appear to be one important neurodegenerative factor. Some genetic changes in individuals with CVD made them more vulnerable to AD. Effective prevention and treatment of CVD can help reduce the risk of AD.

CONCLUSION: HF, AF, and CAD were the CVDs with the highest risk of developing AD. The results suggest that changes in cerebral blood perfusion are a principal neuropathological event that leads to genetic alterations that end in AD.},
}

@article {pmid42474014,
year = {2026},
author = {Yu, Y and Zhao, H and He, Y and Zhao, J and Yang, X and Liu, X and Cheng, X},
title = {Therapeutic Effects of the Traditional Chinese Formula Qifuyin on Cognition, Lipid Metabolism, and Gut Microbiota in ApoE4 Mice.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073453341260621182306},
pmid = {42474014},
issn = {1875-5402},
abstract = {INTRODUCTION: Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Qifuyin is a promising herbal formula used clinically for cognitive decline, but its effects on ApoE4-associated cognitive and systemic phenotypes remain unclear. This study aimed to evaluate the effects of Qifuyin on cognitive performance in ApoE4 transgenic mice and to preliminarily explore its associations with lipid metabolism and gut microbiota alterations.

METHODS: Ten-month-old ApoE4 transgenic mice were treated with Qifuyin by gavage for 321 days, once daily for the first 123 days and once every two days thereafter. Cognitive function was assessed using the step-down test, novel object recognition test (NORT), and Morris water maze test (MWM). Aging- and frailty-related phenotypes were evaluated using senescence grading scores. Serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels were measured to assess lipid metabolism. Gut microbiota composition and functional profiles were analyzed by 16S rRNA and metagenomic sequencing.

RESULTS: Qifuyin treatment significantly reduced error counts and prolonged latency in the stepdown test, increased the 24h preference index in the NORT, shortened escape latency, and increased platform crossings in the MWM in ApoE4 transgenic mice. High-dose Qifuyin reduced aging scores in males and in all doses in females and in the pooled dataset. Qifuyin decreased serum TG and ApoB levels, and increased serum HDL-C levels. 16S rRNA sequencing indicated that Qifuyin increased alpha diversity and shifted beta diversity toward the control profile. At the phylum level, Qifuyin altered the relative abundances of Firmicutes, Bacteroidota, Cyanobacteria, and Synergistota. At the family and genus levels, Qifuyin treatment was associated with increased abundances of Helicobacteraceae, Bacteroidaceae, Helicobacter, and Bacteroides, and a reduced abundance of Ruminococcaceae. Metagenomic annotation analysis showed altered abundances of K02003, K06147, COG1961, CBM37, and GH35-related features.

DISCUSSION: These findings suggest that Qifuyin may benefit ApoE4-associated cognitive and systemic dysfunction through its integrated effects on lipid metabolism and gut microbiota alterations. The microbiota-related changes observed in this study may provide a potential link between peripheral metabolic regulation and cognitive improvement, although their mechanistic significance requires further validation.

CONCLUSIONS: Qifuyin improved cognitive performance and lipid metabolism, and was associated with alterations in gut microbiota composition in ApoE4 transgenic mice. These findings suggest that Qifuyin may exert beneficial effects on cognitive and systemic phenotypes in this model, while the biological significance of specific microbial changes warrants further investigation.},
}

@article {pmid42474555,
year = {2026},
author = {Singh, P and Rath, SL},
title = {Neural network-enhanced investigation of ferroptosis and druggability in early-onset alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42474555},
issn = {1573-7365},
mesh = {*Ferroptosis/physiology/genetics/drug effects ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Humans ; Biomarkers/metabolism ; MicroRNAs/genetics/metabolism ; Oxidative Stress/physiology ; *Neural Networks, Computer ; Machine Learning ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-β protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. This study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic potential biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC- 0.92) in the analysis. The findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic potential biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. This study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related potential biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimer's disease.},
}

*Ferroptosis/physiology/genetics/drug effects
*Alzheimer Disease/metabolism/drug therapy/genetics
Humans
Biomarkers/metabolism
MicroRNAs/genetics/metabolism
Oxidative Stress/physiology
*Neural Networks, Computer
Machine Learning

@article {pmid42474734,
year = {2026},
author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N},
title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42474734},
issn = {1432-1459},
mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; },
abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.

METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.

RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.

CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.},
}

Humans
*Neurofilament Proteins/blood
*Neurodegenerative Diseases/blood/diagnosis
Biomarkers/blood
*Clinical Trials as Topic

@article {pmid42474786,
year = {2026},
author = {Kale, D and Dcunha, BV and Lakshmi, S and Raghu, SV and Elumalai, P},
title = {Neuroprotective potential of marine-derived polysaccharide against Aβ42-induced toxicity in a Drosophila Alzheimer's disease model.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42474786},
issn = {1573-4978},
support = {ICMR (2021 - 11092 No. 52/08/2022 BIO/BMS//ICMR/ ; },
mesh = {Animals ; *Polysaccharides/pharmacology/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/genetics/toxicity ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology ; Drosophila melanogaster/metabolism ; Disease Models, Animal ; Humans ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; *Peptide Fragments/metabolism ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition caused by amyloid β (Aβ42) accumulation, neuroinflammation, oxidative stress and cholinergic dysfunction, resulting in neuronal death and cognitive decline. Excessive Aβ42 accumulation disrupts redox equilibrium, increases reactive oxygen species (ROS), and activates inflammatory and apoptotic pathways. Natural bioactive compounds with immunomodulatory and antioxidant properties are increasingly being explored as possible multi-target therapies. Alkylglycerol (AKG), a lipid-derived immunomodulator, and fucoidan, a sulfated polysaccharide found in brown algae, have both shown neuroprotective properties. This study examines the effectiveness of Fucoidan and AKG in preventing Aβ42-induced diseases in a Drosophila melanogaster model, both individually and in combination.

METHODOLOGY: Transgenic Drosophila expressing human Aβ42 in the brain were divided into control, Aβ42, Fucoidan-treated, AKG-treated, and combination-treated groups. Oxidative stress indicators such as nitric oxide (NO), hydrogen peroxide (H2O₂), malondialdehyde (MDA), and total ROS were measured using biochemical tests. To evaluate redox reactions, the activity of the antioxidant enzymes glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were evaluated. Cholinergic function was assessed by measuring acetylcholinesterase (AChE) activity. The analysis of gene expression focused on genes linked with oxidative stress (SOD, CAT, PHPGx, TRx1), inflammatory markers (TNFα, TNFαR), apoptotic regulator p53, and neurogenesis-related genes (Wnt pathway, SOX2, Nanog).

RESULTS AND DISCUSSION: Aβ42 expression disrupted neurogenic signaling and cholinergic balance while markedly increasing oxidative markers and inflammatory mediators. Although AKG and fucoidan separately decreased inflammation and oxidative stress, the combination treatment yielded the biggest results. Dual therapy increased the activity of antioxidant enzymes, decreased the activity of AChE, downregulated TNFα and p53, and restored the expression of Wnt, SOX2, and Nanog. These results demonstrate the translational potential of Fucoidan and AKG act for AD care by showing that their combined treatment helps to restore redox stability, suppress inflammation, boost neurogenesis, and mitigate Aβ42-induced neurotoxicity.},
}

Animals
*Polysaccharides/pharmacology/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Amyloid beta-Peptides/metabolism/genetics/toxicity
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology
Drosophila melanogaster/metabolism
Disease Models, Animal
Humans
Reactive Oxygen Species/metabolism
Animals, Genetically Modified
*Peptide Fragments/metabolism
Antioxidants/pharmacology

@article {pmid42469568,
year = {2026},
author = {Kaushik, S and Fatima, JE and Raheem, A and Barbhuiya, MA and Thirupathi, AT and Singh, LP and Khan, PA and Aparna, TN and Pramanik, S and Shahid, MAA},
title = {Nanomedicine targeting neuroinflammatory pathways in Alzheimer's disease: a new frontier in inflammopharmacology.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42469568},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative illness characterized by progressive cognitive impairment, synaptic compromise, and relentless neuroinflammation. Increasing evidence suggests that neuroinflammatory cascades orchestrated by microglial activation, astrocytic malfunction, cytokine hyperproduction, and inflammasome signalling are at the core of AD pathogenesis. Conventional anti-amyloid and cholinergic treatments are only symptomatic and neglect the inherent neuroimmune dysregulation. Nanomedicine is a revolutionary frontier in inflammopharmacology, which enables the accurate modulation of neuroinflammatory circuits and enhanced brain delivery of medicines. Nanocarriers designed by engineering, including liposomes, polymeric nanoparticles, dendrimers, and exosomes, allow for targeted delivery across the BBB, increase drug bioavailability, and provide controlled release. The nano-systems are capable of inhibiting pro-inflammatory signalling, such as NF-κB and MAPK pathways, reducing oxidative stress, and enhancing microglial M2 polarization and thus restoring neuronal homeostasis. Recent developments in surface-functionalized and stimuli-responsive nanoplatforms further enable active targeting through receptor-mediated pathways and theranostic imaging in real-time. Comparative studies show that interventions based on nanocarrier-based therapies enhance therapeutic efficacy and safety profiles in preclinical AD models. Future directions include integrating AI-driven nano-design, gene and siRNA delivery, and precision neuropharmacology to enable personalized anti-inflammatory therapies. Substantial progress, translational challenges remain regarding long-term biocompatibility, large-scale production, and clinical validation. Nanomedicine against neuroinflammatory pathways represents a new paradigm for Alzheimer's treatment, linking molecular pharmacology and sophisticated nanotechnology to next-generation neuroinflammatory medicine.},
}

@article {pmid42470923,
year = {2026},
author = {Aydoğdu, GS and Ağagündüz, D and Roviezzo, F and Romano, B and Capasso, R},
title = {Therapeutic potential of curcumin in Alzheimer's disease: Multi-target mechanisms of action, experimental and clinical evidence, safety aspects.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {202},
number = {},
pages = {119776},
doi = {10.1016/j.biopha.2026.119776},
pmid = {42470923},
issn = {1950-6007},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impaired cognitive functions; its prevalence is increasing with the growth of the global elderly population. Unfortunately, early diagnostic and treatment methods developed by modern medicine have limited effectiveness for this disease. This situation has increased interest in natural ingredients, such as curcumin, which have beneficial effects on health. Some preclinical studies evaluating the efficacy of curcumin in Alzheimer's disease suggest that it may have preventive, protective, and therapeutic effects through various mechanisms, including anti-amyloidogenic effects, improvement of tau pathology, cholinesterase inhibition, anti-inflammatory and antioxidant effects, metal chelation, microbiota modulation, and epigenetic regulation. Similarly, some preclinical studies indicate that curcumin-based probes may offer a promising approach to the diagnosis of Alzheimer's disease. However, inconsistencies exist between preclinical and clinical studies. Curcumin's low bioavailability and high systemic elimination may be among the most significant causes of these inconsistencies. It is also thought that this situation may be related to differences and limitations in preclinical and clinical study designs. There is a need for preclinical studies that follow comprehensive, standardized protocols and for larger-scale, long-term, well-designed clinical trials to evaluate the effectiveness of curcumin in the early diagnosis, prevention, and treatment of Alzheimer's disease. In addition, potential risks, such as the toxicological effects of curcumin with increased bioavailability and curcumin-drug interactions in Alzheimer's patients, should be evaluated.},
}

@article {pmid42471071,
year = {2026},
author = {Hu, K and Gao, W and Pan, J and Xu, X and You, P and Li, K and Yang, G and Wang, D and Jiang, M and Wang, X and Zhao, Y and Xu, Y},
title = {Ginkgo biloba extract 50 alleviates memory and synaptic plasticity deficits by inhibiting neuroinflammation via the blockage of ATP-P2X7R axis in presenilin 1/2 conditional double knockout mice.},
journal = {Journal of ethnopharmacology},
volume = {372},
number = {},
pages = {122199},
doi = {10.1016/j.jep.2026.122199},
pmid = {42471071},
issn = {1872-7573},
abstract = {Ginkgo biloba L. has been widely utilized in traditional Chinese medicine for its potential to enhance memory-related functions. In traditional medical practices, it is also commonly prescribed for conditions associated with cognitive decline and age-related disorders. These ethnopharmacological uses are closely linked to neurodegenerative disorders, in which neuroinflammation plays a central role. Ginkgo biloba has shown anti-inflammatory and neuroprotective properties, yet its underlying mechanisms in modulating neuroinflammation are still not fully understood.

AIM OF THE STUDY: Neuroinflammation is critically involved in cognitive impairment and neurodegenerative diseases, while therapeutic options remain limited. Ginkgo biloba extract 50 (GBE50) is a standardized formulation with potential neuroprotective properties. This study aimed to assess its effects on neuroinflammation-associated cognitive dysfunction and to clarify the mechanisms involved.

METHODS: Presenilin 1/2 conditional double knockout mice served as a cognitive impairment model, with behavioral tests used to evaluate cognitive function. The constituents of GBE50 were identified by UPLC-Q-TOF-MS, and ATP content was quantified using biochemical assays. The expression of P2X7 receptor, NLRP3 inflammasome-related proteins, inflammatory cytokines, and synaptic markers was determined at both mRNA and protein levels using qRT-PCR and Western blotting. Microglial activation and P2X7R distribution were assessed via immunofluorescence, and hippocampal synaptic plasticity was examined using electrophysiological recordings.

RESULTS: Using UPLC-Q-TOF-MS, 51 compounds were characterized in GBE50, mainly flavonoids and terpene lactones, which are likely responsible for its biological activities. Treatment with GBE50 markedly alleviated cognitive impairment in PS cDKO mice. It downregulated P2X7R and key components of the NLRP3 inflammasome (NLRP3, NEK7, Caspase-1, and ASC), while also reducing the transcription of pro-inflammatory cytokines including Il-1β, Il-18, and Tnf-α. In parallel, GBE50 restored synaptic protein levels and improved long-term potentiation deficits.

CONCLUSION: Collectively, our findings suggest that modulation of the ATP-P2X7R-NLRP3 axis contributes to the neuroprotective effects of GBE50 in AD, highlighting this pathway as a promising therapeutic target for preventing AD-related neurodegeneration.},
}

@article {pmid42471087,
year = {2026},
author = {Yao, M and Liu, A and Xing, L and Song, J and Yang, Y and Yue, X and Li, H},
title = {Neurovascular unit senescence as a driver of blood-brain barrier dysfunction in Alzheimer's disease：Mechanisms, consequences, and therapeutic implications.},
journal = {Ageing research reviews},
volume = {121},
number = {},
pages = {103260},
doi = {10.1016/j.arr.2026.103260},
pmid = {42471087},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder (NDD), with ageing as its primary risk factor. Cellular senescence, characterized by permanent cell-cycle arrest, apoptosis resistance and acquisition of the senescence-associated secretory phenotype (SASP), is the cellular hallmark of ageing. Recent evidence indicates that blood-brain barrier (BBB) dysfunction precedes cognitive decline and pathological protein deposition, representing an early event in AD, with the neurovascular unit (NVU) providing the structural and functional basis of the BBB. Mounting evidence shows that the core NVU cells-brain microvascular endothelial cells (BMECs), pericytes and astrocytes-enter senescence under AD-related conditions. SASP factors released by these cells disrupt BBB junction proteins and trans-BBB transport systems, and propagate senescence within the NVU via paracrine signaling. Peripheral inflammatory mediators and immune cells then traverse the compromised BBB, aggravating AD pathology, while accumulating Aβ, tau and reactive oxygen species (ROS) reciprocally accelerate NVU senescence, constituting a proposed vicious cycle. At the molecular level, the cGAS-STING pathway concurrently drives senescence maintenance, SASP induction and type I interferon (IFN-I)-mediated downregulation of BBB junction proteins, serving as a key convergence point linking NVU senescence to BBB injury. From the NVU perspective, this review systematically examines how cellular senescence drives BBB dysfunction and AD progression, clarifies the role of cGAS-STING as a molecular node, and discusses therapeutic strategies targeting NVU senescence to preserve BBB integrity, aiming to offer new insights into AD mechanisms and treatment.},
}

@article {pmid42471719,
year = {2026},
author = {Yamada, K and Ishida, K and Sakamoto, A and Shimada, H and Watanabe, M and Shimojo, M and Igarashi, H and Iwatsubo, T},
title = {AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00977-7},
pmid = {42471719},
issn = {1750-1326},
support = {JP23wm0625001//AMED/ ; 23H0279//Japan Society for the Promotion of Science/ ; 25K10766, 20K21568, 18H02762//Japan Society for the Promotion of Science/ ; 2023-23012//Niigata University/ ; },
abstract = {BACKGROUND: The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.

METHODS: Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.

RESULTS: PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.

CONCLUSIONS: Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.},
}

@article {pmid42471753,
year = {2026},
author = {Travison, TG and Davis-Plourde, K and Goldfeld, KS and Li, F and Lou, Y and Monin, JK and Taljaard, M and Turner, J and Vranceanu, AM and Allore, HG},
title = {The design of embedded pragmatic clinical trials: methodological developments and statistical lessons learned from the first cycle of the NIA IMPACT collaboratory.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71660},
pmid = {42471753},
issn = {1552-5279},
support = {U54AG063546/NH/NIH HHS/United States ; },
mesh = {Humans ; *Pragmatic Clinical Trials as Topic/methods ; *Research Design ; United States ; National Institute on Aging (U.S.) ; *Alzheimer Disease/therapy ; },
abstract = {INTRODUCTION: The National Institute on Aging-funded IMbedded Pragmatic Alzheimer's disease and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory was established to build capacity for conducting embedded pragmatic clinical trials (ePCTs) within healthcare systems for people living with dementia and their care partners. Here we present methodology and describe lessons learned from the first five years of IMPACT's Design and Statistics Core (DSC).

METHODS: The DSC assembled a multidisciplinary team focused on advancing the design, analysis, and implementation of ePCTs.

RESULTS: The DSC developed and disseminated methods for design and sample size of cluster randomized designs with complex correlation structures; guidance for pilot ePCTs; approaches to patient-care partner ePCTs; approaches to testing health-equity-relevant hypotheses; and guidance for training quantitative and clinical scientists developing ePCTs.

DISCUSSION: Key gaps remain in applying dyadic designs and when studying heterogeneity of treatment effects, which will be major priorities for the next funding cycle.},
}

Humans
*Pragmatic Clinical Trials as Topic/methods
*Research Design
United States
National Institute on Aging (U.S.)
*Alzheimer Disease/therapy

@article {pmid42471754,
year = {2026},
author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK},
title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71675},
pmid = {42471754},
issn = {1552-5279},
support = {//Johnson & Johnson/ ; },
mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; },
abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.},
}

Animals
*Positron-Emission Tomography/methods
*DNA-Binding Proteins/metabolism
*Brain/diagnostic imaging/metabolism
Rats
Mice
Humans
Male
Disease Models, Animal
TDP-43 Proteinopathies/diagnostic imaging
*Radiopharmaceuticals/pharmacokinetics
Fluorine Radioisotopes

@article {pmid42472492,
year = {2026},
author = {Damirchi, EK and Barani, A and Hamidi, SM and Ebrahimzadeh, MA},
title = {Melatonin hybrids as multifunctional therapeutic agents: A comprehensive review.},
journal = {European journal of medicinal chemistry},
volume = {318},
number = {},
pages = {119156},
doi = {10.1016/j.ejmech.2026.119156},
pmid = {42472492},
issn = {1768-3254},
abstract = {Compound hybridization has received attention due to its potential to address several diseases, including neurological disorders, cancer, infectious diseases, and others. Melatonin is a hormone with antioxidant, anti-inflammatory, and neuroprotective effects. Some drug design research has focused on synthesizing hybrid molecules in which melatonin is hybridized with other pharmacologically active compounds to increase therapeutic efficacy and reduce toxicity. These hybrids demonstrate improved binding affinity, selectivity, and pharmacokinetic characteristics compared to their separate components. This review shows the pharmacological assessment and therapeutic potential of diverse melatonin-based hybrids. These hybrids have exhibited significant efficacy in the treatment of complex diseases such as Alzheimer's disease, cancer, and inflammatory disorders. Hybridization leads to the synthesis of a new generation of structures that represent a promising therapeutic approach for disease treatment.},
}

@article {pmid42472573,
year = {2026},
author = {Yanagisawa, D and Ohgita, T and Kawashima, H and Yoshikawa, H and Saito, H and Tooyama, I and Takata, K},
title = {Neurotheranostics in Alzheimer's Disease: Current concepts and experimental strategies.},
journal = {Pharmacology & therapeutics},
volume = {},
number = {},
pages = {109084},
doi = {10.1016/j.pharmthera.2026.109084},
pmid = {42472573},
issn = {1879-016X},
abstract = {In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.},
}

@article {pmid42472714,
year = {2026},
author = {Khan, M and Khan, T and Tariq, A},
title = {From biomarker expansion to equitable implementation in mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42472714},
issn = {1590-3478},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; },
abstract = {The expanding role of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease diagnosis represents a major shift toward biologically driven dementia care. In response to the article by Poli et al., we discuss important considerations regarding the broader implementation of CSF biomarker testing in patients with mild cognitive impairment (MCI), particularly in the era of emerging anti-amyloid therapies. While biomarker-guided approaches may improve identification of atypical or non-amnestic Alzheimer's disease presentations, widespread adoption remains limited by disparities in diagnostic infrastructure, standardized testing availability, expertise in lumbar puncture procedures, and longitudinal monitoring capacity across healthcare systems. In addition, expanded eligibility for anti-amyloid therapies introduces challenges related to patient selection, treatment accessibility, and equitable allocation of healthcare resources. Ethical considerations surrounding biomarker disclosure and prognostic uncertainty also warrant continued discussion. We emphasize the need for future studies evaluating accessibility, cost-effectiveness, and standardized patient selection frameworks to support equitable integration of biomarker-guided dementia care into routine neurological practice.},
}

Humans
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/diagnosis/cerebrospinal fluid